Crf antagonists and heterobicyclic compounds

ABSTRACT

CRF antagonists comprising as an active ingredient, the compound of formula (I)  
                 
 
wherein A ring is 5-6 membered mono-cyclic ring which may be substituted; B ring is 5-7 membered unsaturated mono-heterocyclic ring which may be contained another 1-2 of hetero atom(s) and substituted by another substituents; W 1  and W 2  is carbon atom or nitrogen atom; Z is NR 3 , oxygen atom, sulfur which may be oxidized or CR 4 R 5 ; R 1  is alkyl, alkenyl or alkynyl that may be substituted, amino which may be protected, hydroxyl which may be protected, S(O) n R 6 , COR 7 , or cyclic group which may be substituted; R 2  is unsaturated cyclic group which may be substituted.

TECHNICAL FIELD

The present invention relates to a Corticotropin Releasing Factorantagonist, a novel bi-heterocyclic ring compound, a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof, and apharmaceutical comprising them as an active ingredient. For more detail,the present invention relates to a Corticotropin Releasing Factorantagonist comprising a compound of formula (I):

wherein all symbols are as hereinafter defined;

as an active ingredient and a novel bi-heterocyclic ring compound offormula (I-A):

wherein all symbols are as hereinafter defined;

a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof, and a pharmaceutical comprising them as an active ingredient.

BACKGROUND ART

Corticotropin Releasing Factor (CRF) was a peptide comprising 41 aminoacid residues and isolated from ovine hypothalamic in 1981. It wassuggested that CRF was released from hypothalamic and controlled asecretion of adrenocorticotropic hormone (ACTH) from hypophysis[Science, 218, 377-379(1982)].

ACTH, which is released by a stimulation of CRF, stimulates a secretionof cortisol from adrenal cortex, and relates to a systemic action forreproduction, growth, gastrointestinal function, inflammation, immunesystem, nervous system etc. Consequently, CRF is believed to plays arole as a regulator of these functions. In view of these, a relationshipof CRF and a central nervous system disease or a neuropsychiatricdisorder has gotten a lot of attention.

On the other hand, the depression patients and the anxiety disorderpatients increase, and the number also of depression patients with theslight illness increases recently. Moreover, an aged patient iscommanding a majority in the depression patient. Under thesecircumstances, from the earliness of the appearance of the effect andrespect of the side effect, psychiatric and neurologic disorderstreatment used easily is requested more and more.

Currently, for the treatment of psychiatric and neurologic disorders,for example, tricyclic antidepressants, tetracyclic antidepressants,monoamine oxidase inhibitors, serotonin and noradrenaline reuptakeinhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), etc.as antidepressant are used. However, the therapeutic gain is not enough;it will take a long time by the time the effect appears; drowsiness, adryness of the mouth and constipation and difficulty feelings inmicturition etc. are seen as a side effect. As an antianxiety agent,such as benzodiazepine anxiolytic, thienodiazepine anxiolytic,non-benzodiazepine anxiolytic etc. are used. However, the therapeuticgain is not also enough; decrease in mental movement function anddecrease in concentration and attention power, drowsiness, stagger,dizziness, headache, amnesia, etc. are seen as a side effect.

It is expected to use a compound having an activity of CRF antagonistfor the treatment of depression and anxiety disorders. For example, inpamphlet of WO 02/53565, a compound of formula (A):

wherein X^(A) and Y^(A) each independently, is carbon or nitrogen andboth are not nitrogens at the same time; W^(A) is carbon or nitrogen;U^(A) and Z^(A) each independently, is CR^(2A), NR^(13A), nitrogen,oxygen, sulfur, C═O or C═S;

is a single bond or a double bond;

is C4-6 carbocyclic ring or 4-6 membered heterocyclic ring containing atleast one of nitrogen, oxygen and sulfur and these rings areunsubstituted or substituted by 1-3 of substitutes selected from C1-4alkyl, C1-4 alkoxy, a halogen atom and CF₃;

R^(1A) is (i) C1-8 alkyl which is unsubstituted or substituted by 1-5 ofR^(14A), (ii) C2-8 alkenyl which is unsubstituted or substituted by 1-5of R^(14A), (iii) C2-8 alkynyl which is unsubstituted or substituted by1-5 of R^(14A), (iv) NR^(4A)R^(5A), (v) OR^(6A), (vi) SH, (vii)S(O)_(n)R^(7A), (viii) COR^(6A), (ix) COOR^(6A), (x) CONR^(4A)R^(5A),(Xi) NR^(8A)CO^(6aA), (xii) NR^(8A)COOR^(6A), (xiii)NR^(8A)CONR^(4A)R^(5A), (xiv) C3-15 mono- or bi-carbocyclic ring whichis unsubstituted or substituted by 1-5 of R^(15A), (xv) 3-15 memberedmono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 ofoxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substitutedby 1-5 of R^(15A);

R^(3A) is (i) C5-10 mono- or bi-carbocyclic ring substituted by 1-5 ofR^(16A) or (ii) 5-10 membered mono- or bi-heterocyclic ring containing1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) substitutedby 1-5 of R^(16A); was described.

On the other hand, as bi-heterocyclic ring compound, for example, inpamphlet of WO 97/11946, a compound of formula (B):

wherein R^(11B) is a hydrogen, lower alkyl, pyridyl, furyl, thienyl,phenyl which may be substituted by lower alkyl or phenylthio, N-loweralkyl pyrrolyl or pyrazinyl; R^(12B) is a hydrogen, a halogen atom,phenyl, phenyl which may be substituted by substituents selected by ahalogen atom, phenylthio and trifluoromethyl and nitro, or phenylsubstituted by lower alkoxy and phenylthio; R^(13B) is a hydrogen, loweralkyl which may be substituted by oxo, ethylenedioxy, lower alkanoyloxy,lower alkoxy, lower alkylthio, carboxyl, halogen or thienyl, loweralkenyl, cycloalkyl, phenyl, furyl or thienyl which may be substitutedby 1-3 of lower alkyl, halogen and lower alkoxy; R^(14B) is a hydrogen,carboxyl, lower alkoxycarbonyl, nitro, a halogen atom or lower alkylsubstituted by lower alkoxy carbonyl or alkali metal salt residue ofcarboxylic acid; or R^(13B) and R^(14B) were taken together, may beformed lower alkylene; R^(15B) is a hydrogen, alkali metal atom, loweralkyl, phenyl which may be substituted by 1-3 of lower alkyl and loweralkoxy, pyridyl, quinolyl or isoquinolyl which may substituted by loweralkyl or halogen; A^(B) is bond or lower alkylene;

was described as analgesic drug,

in pamphlet of WO 01/32632, a compound of formula (C):

wherein X^(1C) is O or NH; L^(C) is bond or C1-6 alkylene chainoptionally interrupted by O, S, SO, SO₂ or NH and optionally substitutedon alkylene carbon by fluoro, hydroxyl, C1-4 alkoxy or oxo; R^(1C) isunsubstituted or substituted carbocyclic ring or heterocyclic ring;R^(2C) is a hydrogen, a halogen atom, carboxyl, cyano, SCH₂CH, orX^(2C)—R^(5C) in which X^(2C) is bond, O, S, SO, SO₂ or NH, R^(5C) isC1-8 alkyl, C3-10 cycloalkyl, halo(C1-6) alkyl, hydroxyl(C1-6)alkyl,dihydroxy(C1-6)alkyl, phenyl or phenyl(C1-4)alkyl in which phenyl isunsubstituted or substituted by one or two substituents selectedindependently from a halogen atom, C1-4 alkyl and C1-4 alkoxy, etc.;R^(3C) and R^(4C) each independently is C1-4 alkyl or together with thecarbon atoms to which they are attached form unsubstituted orsubstituted carbocyclic ring or heterocyclic ring;

was described as mGluR1 antagonist.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide an agent which iseasily handled and has potent prevention and/or treatment effects in theprevention and/or treatment of psychiatric and neurologic disorders,diseases of peripheral organs or the like.

The present inventors studied intensively in order to solve the aboveproblems, and as a result, found that the object can be achieved by abicyclic heterocyclic ring.

The present invention relates to the followings:

1. A CRF antagonist comprising, as an active ingredient, a compoundrepresented by formula (I):

wherein ring A represents a 5- or 6-membered monocyclic ring which maybe substituted with 1 to 3 substituents selected from a halogen atom,CF₃, OCF₃, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl,carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substitutedwith 1 to 3 substituents selected from a halogen atom, CF₃ and hydroxyl;

ring B represents a 5- to 7-membered monocyclic unsaturated heterocyclicring which may contain 1 or 2 hetero atoms selected from a nitrogenatom, an oxygen atom and/or a sulfur atom which may be oxidized, otherthan the nitrogen atom, W¹ and W² and which may be further substituted;

W¹ and W² each independently, represents a carbon atom or a nitrogenatom;

Z represents —NR³—, in which R³ represents a hydrogen atom, C1-6 alkyl,C2-6 alkenyl or C2-6 alkynyl which each may be substituted, —CO—(C1-6alkyl which may be substituted), —SO₂—(C1-6 alkyl which may besubstituted), an oxygen atom, a sulfur atom which may be oxidized, or—CR⁴R⁵—, in which R⁴ and R⁵ each independently represents a hydrogenatom, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may besubstituted, or R⁴ and R⁵ may be taken together to represent (i) oxo,(ii) C2-5 alkylene in which one carbon atom may be substituted with oneoxygen atom, nitrogen atom or sulfur atom which may be oxidized, whereinthe C2-5 alkylene may be substituted with a substituent(s), or (iii)C1-6 alkylidene which may be substituted;

R¹ represents:

(i) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may besubstituted,

(ii) amino which may be protected,

(iii) hydroxyl which may be protected,

(iv) mercapto which may be protected,

(v) —S(O)_(n)R⁶, in which n represents 1 or 2, and R⁶ represents (a)C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may besubstituted or (b) a cyclic group which may be substituted,

(vi) —COR⁷, in which R⁷ represents (a) a hydrogen atom, (b) C1-15 alkyl,C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (c)hydroxyl which may be protected, (d) amino which may be protected, or(e) a cyclic group which may be substituted, or

(vii) a cyclic group which may be substituted;

R² represents an unsaturated cyclic group which may be substituted, inwhich the substituent may be taken together with R³ to form C2-5alkylene which may be substituted,

a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof

2. A compound represented by formula (I-A):

wherein

represents a ring selected from

(1) cyclic group 1:

and

(2) cyclic group 2:

and ring A may be substituted with 1 to 3 substituents selected from ahalogen atom, CF₃, OCF₃, hydroxyl, mercapto, carboxyl, (C1-6alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may besubstituted with 1 to 3 substituents selected from a halogen atom, CF₃and hydroxyl, and ring B may be further substituted;

R¹ represents:

(i) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may besubstituted,

(ii) amino which may be protected,

(iii) hydroxyl which may be protected,

(iv) mercapto which may be protected,

(v) —S(O)_(n)R⁶, in which n represents 1 or 2, and R⁶ represents (a)C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may besubstituted, or (b) a cyclic ring which may be substituted,

(vi) —COR⁷, in which R⁷ represents (a) a hydrogen atom, (b) C1-15 alkyl,C2-15 alkenyl or C2-15 alkynyl which each may be substituted, (c)hydroxyl which may be protected, (d) amino which may be protected, or(e) a cyclic group which may be substitute, or

(vii) a cyclic group which may be substituted;

R^(1a) represents:

(i) C1-15 alkyl or C2-15 alkenyl which may be substituted withsubstituent group 1,

(ii) NR⁸R⁹, in which R⁸ represents (a) a hydrogen atom or (b) C1-15alkyl or C2-15 alkenyl which each may be substituted with substituentgroup 1, and R⁹ represents (a) a hydrogen atom, (b) C1-15 alkyl or C2-15alkenyl substituted with substituent group 1, (c) —COR¹⁰, in which R¹⁰represents (aa) a hydrogen atom or (bb) C1-15 alkyl or C2-15 alkenylwhich each may be substituted with substituent group 1, (d) —COOR¹⁰, inwhich R¹⁰ has the same meaning as described above, or (e) —CON(R⁸)₂, inwhich R⁸s each independently has the same meaning as described above,

(iii) OR¹⁰, in which R¹⁰ has the same meaning described above,

(iv) SR¹⁰, in which R¹⁰ has the same meaning described above,

(v) S(O)_(n)R¹¹, in which n represents 1 or 2, and R⁶ represents C1-15alkyl or C2-15 alkenyl which each may be substituted with substituentgroup 1, or

(vi) COR¹², in which R¹² represents (a) a hydrogen atom, (b) C1-15 alkylor C2-15 alkenyl which each may be substituted with substituent group 1,(c) —OR¹⁰, in which R¹⁰ has the same meaning as described above, or (d)—NR⁸R⁹, in which R⁸ and R⁹ have the same meanings as described above;

the substituent group 1 represents (1) a halogen atom, (2) CF₃, (3)OCF₃, (4) cyano, (5) nitro, (6) hydroxyl, (7) C1-6 alkoxy, (8) carboxyl,(9) (C1-6 alkoxy)carbonyl, (10) C1-5 acyl, (11) carbamoyl in which anitrogen atom may be protected with 1 or 2 of C1-6 alkyl, (12) C1-6alkylthio, (13) C1-6 alkylsulfonyl, or (14) NR¹³R¹⁴, in which R¹³represents (a) a hydrogen atom, (b) C1-6 alkyl, or (c) C2-6 alkenyl, andR¹⁴ represents (a) a hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl,(d) —COR¹⁵, in which R¹⁵ represents (aa) a hydrogen atom, (bb) C1-6alkyl or (cc) C2-6 alkenyl, (e) —COOR¹⁵, in which R¹⁵ has the samemeaning as described above, or (f) —CON(R¹⁶)₂, in which R¹⁶s eachindependently represents a hydrogen atom or C1-6 alkyl;

Z^(a) represents —NR³—, in which R³ represents a hydrogen atom, C1-6alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted,—CO—(C1-6 alkyl which may be substituted), —SO₂—(C1-6 alkyl which may besubstituted), an oxygen atom, a sulfur atom which may be oxidized, or—CR⁴R⁵—, in which R⁴ and R⁵ each independently represents a hydrogenatom, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be-substituted, or R⁴ and R⁵ may be taken together to represent (i) oxo,(ii) C2-5 alkylene in which one carbon atom may be substituted with oneoxygen atom, nitrogen atom or sulfur atom which may be oxidized, whereinthe C2-5 alkylene may be substituted with a substituent(s), or (iii)C1-6 alkylidene which may be substituted;

R^(2a) represents (1) a C5-12 monocyclic or bicyclic unsaturatedcarbocyclic ring which may be substituted, (2) pyridine which may besubstituted, (3) a bicyclic heterocyclic ring which may be substituted,in which benzene and a 5- or 6-membered monocyclic heterocyclic ring arefused, (4) a bicyclic heterocyclic ring which may be substituted, inwhich a pyridine ring and a C5-6 monocyclic carbocyclic ring are fused,or (5) a bicyclic heterocyclic ring which may be substituted, in which apyridine ring and a 5- or 6-membered monocyclic heterocyclic ring arefused,

a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof.

3. The compound according to the above 2,

wherein the ring

is

wherein all symbols have the same meanings as described in claim 2,

a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof

4. The compound according to the above 2, wherein R¹ is amino which maybe protected, or R^(1a) is NR⁸R⁹, in which R⁸ and R⁹ have the samemeanings as described in the above 2, a salt thereof, an N-oxidethereof, a solvate thereof or a prodrug thereof

5. The compound according to the above 2, wherein Z^(a) is —NR³—, inwhich R³ has the same meaning as described in the above 2, a saltthereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

6. The compound according to the above 2, wherein Z^(a) is—CR^(4b)R^(5b)—, in which R^(4b) and R^(5b) are taken together torepresent C2-5 alkylene in which one carbon atom may be substituted withone oxygen atom, nitrogen atom or sulfur atom which may be oxidized,wherein the C2-5 alkylene may be substituted with a substituent(s), asalt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof

7. The compound according to the above 2, which is represented byformula (I-A-3):

R^(1-A) represents amino which may be protected with 1 or 2 of C1-15alkyl which may be substituted;

G^(a1)s each independently represents a hydrogen atom, a halogen atom,CF₃, OCF₃, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl,carbamoyl, nitro, cyano, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy or C1-6 alkylthio which each may be substituted with 1 or 2substituents selected from a halogen atom, CF₃ and hydroxyl;

G² represents a hydrogen atom, C1-15 alkyl, C2-15 alkenyl or C2-15alkynyl which may be substituted, hydroxyl which may be protected,cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, a halogenatom, CF₃, or cyano; and other symbols have the same meanings as in theabove 2,

a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof.

8. The compound according to the above 2, which is represented byformula (I-A-4):

R^(1a-A) represents NR^(8A)R^(9A), in which one of R^(8A) and R^(9A)represents C1-15 alkyl which may be substituted with the substituentgroup 1 and another represents a hydrogen atom or C1-15 alkyl which maybe substituted with the substituent group 1, wherein the substituentgroup 1 has the same meaning as in the above 2;

G^(a2)s each independently represents a hydrogen atom, a halogen atom,CF₃, OCF₃, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl,carbamoyl, nitro, cyano, oxy, oxo, or C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substitutedwith 1 or 2 substituents selected from a halogen atom, CF₃ and hydroxyl;and other symbols have the same meanings as described in the above 2 or7,

a salt thereof; -an N-oxide thereof, a solvate thereof or a prodrugthereof

9. The compound according to the above 2, which is:

(1)N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(2)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(3)N⁵-(2-chloro-4-methoxyphenyl)-6-ethyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(4)N²-(2-chloro-4-methoxyphenyl)-N²-ethyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,

(5)N⁵-(2-chloro-4-methoxyphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(6)N²-allyl-N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,

(7)6-methyl-N⁵-[2-methyl-4-(trifluoromethoxy)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(8)N⁷-butyl-N⁵-(2-chloro-4-methoxyphenyl)-N⁷-ethyl-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(9)N⁵-(2-ethyl-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(10)6-methoxy-N⁵-(4-methyl-2-vinylphenyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,or

(11)N⁵-(2-ethyl-4-methylphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

a salt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof

10. A pharmaceutical composition comprising, as an active ingredient,the compound represented by formula (I-A) according to the above 2, asalt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof.

11. The pharmaceutical composition according to the above 10, which is aCRF antagonist.

12. The pharmaceutical composition according to the above 10, which isan agent for preventing and/or treating CRF mediated diseases.

13. The pharmaceutical composition according to the above 12, whereinthe CRF mediated diseases are psychiatric and neurologic disorders ordigestive diseases.

14. The pharmaceutical composition according to the above 13, whereinthe psychiatric and neurologic disorders or the digestive diseases aremood disorders, anxiety disorders, stress-related disorders, eatingdisorders, symptom caused by psychotropic substance or dependencythereon, organic mental disorder, schizophrenic disorder,attention-deficit hyperactivity disorder or irritable bowel syndrome.

15. The pharmaceutical composition according to the above 14, whereinthe psychiatric and neurologic disorders or the digestive diseases aredepression, mood disorders, eating disorders, drug addiction, drugdependency or irritable bowel syndrome.

16. A medicament comprising a combination of the compound represented byformula (I-A) according to the above 2, a salt thereof, an N-oxidethereof, a solvate thereof or a prodrug thereof with at least oneselected from a tricyclic antidepressant, a tetracyclic antidepressant,a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptakeinhibitor, a selective serotonin reuptake inhibitor, a serotoninreuptake inhibitor, a psychoanaleptic, an antianxiety agent, anantipsychotic agent, a mitochondrial benzodiazepine receptor ligand, anNK1 antagonist, a gastrointestinal promotility agent, a 5-HT₃antagonist, a 5-HT₄ agonist, an anticholinergic agent, an antidiarrhealdrug, a lapactic and an autonomic modulating agent.

17. A method for antagonizing CRF, which comprises administering to amammal an effective amount of the compound represented by formula (I), asalt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof:

wherein all symbols have the same meanings as described in the above 1.

18. A method for preventing and/or treating a CRF mediated disease,which comprises administering to a mammal an effective amount of thecompound represented by formula (I-A), a salt thereof, an N-oxidethereof, a solvate thereof or a prodrug thereof:

wherein all symbols have the same meanings as described in the above 2.

19. Use of the compound represented by formula (I), a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof for themanufacture of a CRF antagonist:

wherein all symbols have the same meanings as described in the above 1.

20. Use of the compound represented by formula (I), a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof for themanufacture of a CRF mediated disease:

wherein all symbols have the same meanings as described in the above 2.

In the present invention, ring

includes, for example,

In the present invention, the 5- or 6-membered monocyclic ring includesa 5- or 6-membered monocyclic carbocyclic ring or monocyclicheterocyclic ring.

The 5- or 6-membered monocyclic carbocyclic ring includes, for example,cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene,cyclohexadiene, and benzene rings.

The 5- or 6-membered monocyclic heterocyclic ring includes a 5- or6-membered monocyclic heterocyclic ring containing 1 to 4 hetero atomsselected from a nitrogen atom, an oxygen atom and/or a sulfur atom whichmay be oxidized. Examples include pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine,oxathiane, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, furazan, thiadiazole, pyran, thiopyran, oxazine,oxadiazine, thiazine and thiadiazine rings.

In the present invention, the 5- to 7-membered monocyclic unsaturatedheterocyclic ring which may contain 1 or 2 hetero atoms selected from anitrogen atom, an oxygen atom and/or a sulfur atom which may beoxidized, other than the nitrogen atom, W¹ and W² and which may befurther substituted includes a 5- to 7-membered monocyclic unsaturatedheterocyclic ring which may be substituted with 1 or 2 substituentsselected from the substituent group 2, always contains one nitrogen atomand may contain 1 or 2 hetero atoms selected from a nitrogen atom, anoxygen atom and/or a sulfur atom which may be oxidized, other than thenitrogen atom, W¹ and W². Examples include pyrrole, imidazole, triazole,pyridine, pyrimidine, pyridazine, triazine, azepine, diazepine, oxazine,oxadiazine, oxazepine, oxadiazepine, thiazine, thiadiazine, thiazepine,and thiadiazepine rings.

In this connection, in ring A and ring B, the total number of thenitrogen atoms contained is 5 or less, and the total number of theoxygen atom and the sulfur atom which may be oxidized contained in ringA and ring B is 2 or less.

In the present invention, the substituent group 2 includes:

(i) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may besubstituted,

(ii) amino which may be protected,

(iii) hydroxyl which may be protected,

(iv) mercapto which may be protected,

(v) —S(O)_(n)R⁶, in which n and R⁶ have the same meanings as describedabove,

(vi) —COR⁷, in which R⁷ has the same meaning as described above,

(vii) a cyclic group which may be substituted, and

(viii) a halogen atom, CF₃, OCF₃, nitro, or cyano.

In the present invention, the sulfur atom which may be oxidized includesS, SO, and SO₂.

In the present invention, the C1-15 alkyl which may be substitutedincludes straight or branched C1-15 alkyl which may be substituted, andexamples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl, which each may besubstituted.

In the present invention, the C2-15 alkenyl which may be substitutedincludes straight or branched C2-15 alkenyl having 1 to 3 double bondswhich may be substituted, and examples include vinyl, propenyl, butenyl,pentenyl, hexenyl, hexadienyl, heptenyl heptadienyl, octenyl,octadienyl, nonenyl, nonadienyl, decenyl, decadienyl, undecenyl,dodecenyl, tridecenyl, tetradecenyl and pentadecenyl, which each may besubstituted.

In the present invention, the C2-15 alkynyl which may be substitutedincludes straight or branched C2-15 alkynyl having 1 to 3 triple bondswhich may be substituted, and examples include ethynyl, propynyl,butynyl, pentynyl, hexynyl, hexadiynyl, heptynyl, heptadiynyl, octynyl,octadiynyl, nonyl, decynyl, undecynyl, dodecynyl, tridecynyl,tetradecynyl and pentadecynyl, which each may be substituted.

In the present invention, the substituent group 1 in “C1-15 alkyl orC2-15 alkenyl which may be substituted with substituent group 1” may besubstituted on 1 to 4 substitutable positions on the C1-15 alkyl orC2-15 alkenyl.

The substituent group 1 includes (1) a halogen atom, (2) CF₃, (3) OCF₃,(4) cyano, (5) nitro, (6) hydroxyl, (7) C1-6 alkoxy, (8) carboxyl, (9)(C1-6 alkoxy)carbonyl, (10) C1-5 acyl, (11) carbamoyl in which anitrogen atom may be protected with 1 or 2 of C1-6 alkyl, (12) C1-6alkylthio, (13) C1-6 alkylsulfonyl, and (14) NR¹³R¹⁴, in which R¹³ is(a) a hydrogen atom, (b) C1-6 alkyl, or (c) C2-6 alkenyl, and R¹⁴represents (a) a hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d)—COR¹, in which R¹⁵ represents (aa) a hydrogen atom, (bb) C1-6 alkyl or(cc) C2-6 alkenyl, (e) —COOR¹⁵, in which R¹⁵ has the same meaningdescribed above, or (f) —CON(R¹⁶)₂, in which R¹⁶s each independentlyrepresents a hydrogen atom or C1-6 alkyl.

In the present invention, the C1-6 alkyl which may be substitutedincludes straight or branched C1-6 alkyl which may be substituted, andexamples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl and hexyl, which each may be substituted.

In the present invention, the C2-6 alkenyl which may be substitutedincludes straight or branched C2-6 alkenyl having one double bond whichmay be substituted, and examples include vinyl, propenyl, butenyl,pentenyl and hexenyl, which each may be substituted.

In the present invention, the C2-6 alkynyl which may be substitutedincludes straight or branched C2-6 alkynyl having one triple bond whichmay be substituted, and examples include ethynyl, propynyl, butynyl,pentynyl and hexynyl, which each may be substituted.

In the present invention, the C2-5 alkylene or the C2-5 alkylene whichmay be substituted includes methylene, methylene, ethylene,trimethylene, tetramethylene, pentamethylene and isomers thereof.

In the present invention, the C1-6 alkylidene which may be substitutedincludes methylidene, ethylidene, propylidene, pentylidene, hexylideneand isomers thereof.

In the present invention, the “C1-6 alkyl which may be substituted”, the“C2-6 alkenyl which may be substituted”, the “C2-6 alkynyl which may besubstituted”, the “C2-5 alkylene which may be substituted”, the “C1-6alkylidene which may be substituted”, the “C1-15 alkyl which may besubstituted”, the “C2-15 alkenyl which may be substituted”, the “C2-15alkynyl which may be substituted” and the “C1-15 alkoxy which may besubstituted” include “substituted or unsubstituted C1-6 alkyl”,“substituted or unsubstituted C2-6 alkenyl”, “substituted orunsubstituted C2-6 alkynyl”, “substituted or unsubstituted C2-5alkylene”, “substituted or unsubstituted C1-6 alkylidene”, “substitutedor unsubstituted C1-15 alkyl”, “substituted or unsubstituted C2-15alkenyl”, “substituted or unsubstituted C2-15 alkynyl” and “substitutedor unsubstituted C1-15 alkoxy”, and the “substituent(s)” include thefollowing substituent group 3.

The substituent group 3 includes (1) a halogen atom, (2) CF₃, (3) OCF₃,(4) cyano, (5) nitro, (6) hydroxyl which may be protected with C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, a cyclic group or a protective grouphaving leaving ability, (7) C1-7 acyl, (8) carbonyl which may beprotected with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a cyclic group,(9) carbamoyl which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl or a cyclic group, (10) thiol which may be protected with C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl or a cyclic group, (11) NR¹⁷R¹⁸, inwhich R¹⁷ represents (a) a hydrogen atom, (b) C1-6 alkyl, (c) C2-6alkenyl, (d) C2-6 alkynyl, or (e) a cyclic group; and R¹⁸ represents (a)a hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e)—COR²⁰, in which R²⁰ represents (aa) a hydrogen atom, (bb) C1-6 alkyl,C2-6 alkenyl or C2-6 alkynyl or (cc) a cyclic group, (f) —COOR²⁰, inwhich R²⁰ has the same meaning as described above, or (g) —CON(R⁷)₂ inwhich R¹⁷s each independently has the same meaning as described above,(12) —S(O)_(n)R¹⁹, in which n has the same meaning as described above,and R¹⁹ represents (a) a hydrogen atom, (b) C1-6 alkyl, C2-6 alkenyl orC2-6 alkynyl or (c) a cyclic group, (13) —COR²⁰, in which R²⁰ has thesame meaning as described above, and (14) a cyclic group which may besubstituted. These substituents may be substituted on 1 to 4substitutable positions. Furthermore, the C1-6 alkyl, C2-6 alkenyl andC2-6 alkynyl in the substituent group 3 may be substituted with asubstituent(s) selected from the substituent group 5, and the cyclicgroup may be substituted with a substituent(s) selected from thesubstituent group 4.

In the present invention, the halogen atom includes fluorine, chlorine,bromine and iodine.

In the present invention, C1-6 alkyl includes, for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl and hexyl.

In the present invention, C2-6 alkenyl includes, for example, vinyl,propenyl, butenyl, pentenyl, hexenyl and hexadienyl.

In the present invention, C2-6 alkynyl includes, for example, ethynyl,-propynyl, butynyl, pentynyl, hexynyl and hexadiynyl.

In the present invention, the hydroxyl which may be protected with C1-6alkyl includes C1-6 alkoxy.

In the present invention, the C1-6 alkoxy includes, for example,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy and hexyloxy.

In the present invention, the C1-15 alkoxy includes, for example,straight or branched C1-15 alkoxy, and examples include methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy,undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy and pentadecyloxy.

In the present invention, the C1-6 alkylthio includes, for example,methylthio, ethylthio, propylthio, isopropylthio, n-butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present invention, the C1-5 acyl includes, for example, formyl,acetyl, propanoyl, butanoyl, 2-methylpropanoyl and pivaloyl.

In the present invention, the C1-7 acyl includes, for example, formyl,acetyl, propanoyl, pivaloyl and benzoyl.

In the present invention, the (C1-6 alkoxy)carbonyl includes, forexample, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present invention, the carbamoyl in which a nitrogen atom may beprotected with 1 or 2 of C1-6 alkyl includes N-(C1-6 alkyl)carbamoyl andN,N-di(C1-6 alkyl)carbamoyl.

In the present invention, the amino which may be protected includesamino protected with 1 or 2 of the following protecting groups, andunsubstituted amino. The amino-protecting groups include (a) C1-15 alkylwhich may be substituted, (b) C2-15 alkenyl which may be substituted,(c) C2-15 alkynyl which may be substituted, (d) a cyclic group which maybe substituted, (e) —COR²¹, in which R²¹ represents (aa) a hydrogenatom, (bb) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may besubstituted or (cc) a cyclic group which may be substituted, (f)—COOR²¹, in which R²¹ has the same meaning as described above, and (g)—CON(R²²)₂, in which R²²s each independently represents (aa) a hydrogenatom or (bb) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each maybe substituted.

In the present invention, hydroxyl which each may be protected includes,for example, (a) C1-15 alkyl which may be substituted, (b) C2-15 alkenylwhich may be substituted, (c) C2-15 alkynyl which may be substituted,(d) a cyclic group which may be substituted, and (e) hydroxyl orhydroxyl protected with a protecting group having leaving ability.Herein, the protecting group having leaving ability includes, forexample, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE),methoxyethoxymethyl (M), 2-tetrahydropyranyl (THP), trimethylsilyl(TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS),t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl(Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc) and2,2,2-trichloroethoxycarbonyl (Troc). Also, the hydroxyl protected withC1-15 alkyl which may be substituted includes C1-15 alkoxy which may besubstituted.

In the present invention, the mercapto which may be protected includesmercapto protected with (a) C1-15 alkyl which may be substituted, (b)C2-15 alkenyl which may be substituted, (c) C2-15 alkynyl which may besubstituted or (d) a cyclic group which may be substituted, andunsubstituted mercapto.

In the present invention, the cyclic group includes a carbocyclic groupand a heterocyclic group. The carbocyclic group includes a C3-12monocyclic or bicyclic carbocyclic group, and examples includecyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,heptalene, perhydroheptalene and bicyclo[3.1.1]heptane ring groups.

The heterocyclic group includes a C3-12 monocyclic or bicyclicheterocyclic ring containing 1 to 4 hetero atoms selected from anitrogen atom, an oxygen atom and/or a sulfur atom which may beoxidized, and examples include oxirane, thiirane, aziridine, oxetane,thietane, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydroazepine,tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine,perhydrooxepine, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine,tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, oxathiane, indoline, isoindoline,dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran,perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene,dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole andbenzotriazole ring groups.

In the present invention, the cyclic group which may be substitutedincludes a carbocyclic group and a heterocyclic group, which each may besubstituted with the substituent group 4. The carbocyclic group and theheterocyclic group include those groups described above.

The substituent group 4 includes (1) C1-6 alkyl, (2) C2-6 alkenyl, (3)C2-6 alkynyl, (4) hydroxyl which may be protected with C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, a cyclic group or a protecting group havingleaving ability, (5) mercapto which may be protected with C1-6 alkyl,C2-6 alkenyl, C2-6 alkynyl or a cyclic group, (6) amino which may beprotected with 1 or 2 groups selected from C1-6 alkyl, C2-6 alkenyl,C2-6 alkynyl and a cyclic group, (7) carbamoyl which may be protectedwith 1 or 2 groups selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyland a cyclic group, (8) sulfamoyl which may be protected with 1 or 2groups selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and a cyclicgroup, (9) carboxyl which may be protected with C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl or a cyclic group, (10) nitro, (11) cyano, (12)amidino, (13) a halogen atom, (14) CF₃, (15) OCF₃, (16) C1-7 acyl, (17)oxo, and (18) thioxo. These substituents may be substituted on 1 to 5substitutable positions. Furthermore, in the substituent group 4, theC1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl may be substituted with asubstituent(s) selected from the substituent group 5, and the cyclicgroup may be substituted with a substituent(s) selected from thesubstituent group 6.

The substituent group 5 includes (1) C1-6 alkoxy, (2) C1-6 alkylthio,(3) a halogen atom, (4) hydroxyl which may be protected with C1-6 alkyl,C2-6 alkenyl, C2-6 alkynyl, a cyclic group, cyclic group-C1-6 alkyl or aprotecting group having leaving ability, (5) CF₃, (6) OCF₃, (7) nitro,(8) cyano, (9) carboxyl, (10) (C1-6 alkoxy)carbonyl, (11)benzyloxycarbonyl, (12) mercapto, (13) amino, (14) C1-6 alkylamino, (15)di(C1-6 alkyl)amino, (16) carbamoyl, (17) N-(C1-6 alkyl)carbamoyl, (18)N,N-di(C1-6 alkyl)carbamoyl, (19) sulfamoyl, (20) N-(C1-6alkyl)sulfamoyl, (21) N-di(C1-6 alkyl)sulfamoyl, (22) C1-7 acyl, and(23) a cyclic group which may be substituted with the substituent group6.

The substituent group 6 includes (1) C1-6 alkyl, (2) C2-6 alkenyl, (3)C2-6 alkynyl, (4) C1-6 alkoxy, (5) C1-6 alkylthio, (6) a halogen atom,(7) CF₃, (8) OCF₃, (9) nitro, (10) cyano, (11) hydroxyl which may beprotected which may be protected with C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, a cyclic group, cyclic group-C1-6 alkyl or a protecting grouphaving leaving ability, (12) carboxyl, (13) (C1-6 alkoxy)carbonyl, (14)benzyloxycarbonyl, (15) mercapto, (16) amino, (17) C1-6 alkylamino, (18)di(C1-6 alkyl)amino, (19) carbamoyl, (20) N-(C1-6 alkyl)carbamoyl, (21)N,N-di(C1-6 alkyl)carbamoyl, (22) sulfamoyl, (23) N-(C1-6alkyl)sulfamoyl, (24) N-di(C1-6 alkyl)sulfamoyl, (25) C1-7 acyl, (26)oxo, and (27) thioxo.

In the present invention, the cyclic group-C1-6 alkyl includescarbocyclic group-C1-6 alkyl and heterocyclic group-C1-6 alkyl, such asC1-6 alkyl substituted with one carbocyclic group and C1-6 alkylsubstituted with one heterocyclic group, respectively. The carbocyclicgroup, the heterocyclic group and the C1-6 alkyl have the same meaningsas described above.

In the present invention, the unsaturated cyclic group which may besubstituted includes an unsaturated carbocyclic group and an unsaturatedheterocyclic group, which each may be substituted with 1 to 5substituents selected from the substituent group 7.

The unsaturated carbocyclic group includes a C5-12 monocyclic orbicyclic unsaturated carbocyclic group, and examples include benzene,pentalene, indene, indane, naphthalene, dihydronaphthalene,tetrahydronaphthalene and azulene ring groups. In this connection, inthe case of the indene, indane, dihydronaphthalene andtetrahydronaphthalene ring groups, the benzene ring in these ring groupsis bound to the group Z.

The unsaturated heterocyclic group includes a 5- to 12-memberedmonocyclic or bicyclic unsaturated heterocyclic group containing 1 to 4hetero atoms selected from a nitrogen atom, an oxygen atom and/or asulfur atom which may be oxidized. Examples include pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, azepine, furan, pyran, oxepine, thiophene, thiopyran,thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine,indole, isoindole, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline,phthalazine, quinoxaline, quinazoline, cinnoline, naphthyridine,benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan,benzothiadiazole, benzotriazole ring groups. In this connection, in thecase of the indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,phthalazine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazoleand benzotriazole ring groups, the benzene ring in these ring groups isbound to the group Z.

The substituent group 7 includes (1) C1-15 alkyl which may besubstituted, (2) C2-15 alkenyl which may be substituted, (3) C2-15alkynyl which may be substituted, (4) hydroxyl which may be protected,(5) mercapto which may be protected, (6) amino which may be protected,(7) carbamoyl which may be protected, (8) sulfamoyl which may beprotected, (9) carboxyl which may be protected, (10) sulfo which may beprotected (—SO₃H), (11) sulfino which may be protected (—SO₂H), (12)nitro, (13) cyano, (14) amidino, (15) imino, (16) a halogen atom, (17) acyclic group which may be substituted, (18) C1-7 acyl, (19) oxo, (20)thioxo and (21) sulfino which may be protected (—SOH). Thesesubstituents may be substituted on 1 to 5 substitutable positions.

In the present invention, the “protecting group” in the “carbamoyl whichmay be protected”, the “sulfamoyl which may be protected”, the “carboxylwhich may be protected”, the “sulfo which may be protected”, the“sulfino which may be protected” and the “sulfino which may beprotected” includes (a) C1-15 alkyl which may be substituted, (b) C2-15alkenyl which may be substituted, (c) C2-15 alkynyl which may besubstituted, and (d) a cyclic group which may be substituted.

In the present invention, the C5-12 monocyclic or bicyclic unsaturatedcarbocyclic ring which may be substituted includes a C5-12 monocyclic orbicyclic unsaturated carbocyclic ring which may be substituted with 1 to5 substituents selected from the above substituent group 7, and examplesinclude benzene, pentalene, indene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene and azulene rings. In thisconnection, in the case of the indene, indane, dihydronaphthalene andtetrahydronaphthalene rings, the benzene ring in these rings is bound toZ^(a).

In the present invention, the substituent in the pyridine which may besubstituted includes 1 to 4 substituents selected from the abovesubstituent group 7.

In the present invention, the bicyclic heterocyclic ring which may besubstituted, in which benzene and a 5- or 6-membered monocyclicheterocyclic ring, includes a bicyclic heterocyclic ring which may besubstituted with 1 to 5 substituents selected from the above substituentgroup 7, in which benzene and a 5- or 6-membered monocyclic heterocyclicring are fused, and examples include indole, isoindole, indoline,isoindoline, benzofuran, isobenzofuran, dihydrobenzofuran,dihydroisobenzofuran, benzothiophene, isobenzothiophene,dihydrobenzothiophene, dihydroisobenzothiophene, chroman and isochromanrings, in which the benzene ring in these rings is bound to the groupZ^(a).

In the present invention, the bicyclic heterocyclic ring which may besubstituted, in which a pyridine ring and C5-6 monocyclic carbocyclicring are fused, include a bicyclic heterocyclic ring which may besubstituted 1 to 5 substituents selected from the above substituentgroup 7, in which a pyridine ring and a C5-6 monocyclic carbocyclic ringare fused, and examples include quinoline, isoquinoline,tetrahydroquinoline and tetrahydroisoquinoline rings. In the case of thetetrahydroquinoline and tetrahydroisoquinoline rings, the pyridine ringbinds to the group Z^(a).

In the present invention, the bicyclic heterocyclic ring which may besubstituted, in which a pyridine ring and a 5- or 6-membered monocyclicheterocyclic ring are fused, includes a bicyclic heterocyclic groupwhich may be substituted with 1 to 5 substituents selected from thesubstituent group 7, in which a pyridine ring and a 5- or 6-memberedmonocyclic heterocyclic ring are fused, and examples includenaphthyridine.

In the present invention, the C3-6 cycloalkyl which may contain 1 or 2hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogenatom includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane,oxetane, tetrahydrofuran, tetrahydropyran, thiirane, thietane,tetrahydrothiophene, tetrahydrothiopyran, aziridine, azetidine,pyrrolidine, piperidine, morpholine and thiomorpholine.

In the present invention, preferred rings as ring A are cyclopentane,cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene,benzene, pyrroline, pyrrolidine, pyrrole, imidazoline, imidazolidine,imidazole, pyrazole, triazoline, triazolidine, triazole, tetrazoline,tetrazolidine, tetrazole, dihydrofuran, tetrahydrofuran, furan,dihydrothiophene, tetrahydrothiophene, thiophene, dihydrofurazan,tetrahydrofurazan, furazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine) and thiadiazole. Particularly, cyclopentane,cyclopentene, pyrrole, imidazole, pyrazole, triazole, tetrahydrofuran,furan, furazan and thiadiazole are preferred.

In the present invention, ring A is preferably unsubstituted orsubstituted with 1 or 2 substituents selected from a halogen atom, CF₃,OCF₃, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl,nitro, cyano, oxo, and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy or C1-6 alkylthio which each may be substituted with 1 or 2substituents selected from a halogen atom, CF₃ and hydroxyl. Ring A ismore preferably unsubstituted ring A, or ring A substituted with 1 or 2substituents selected from a halogen atom, CF₃, hydroxyl, carboxyl,(C1-6 alkoxy)carbonyl, cyano, oxo, and C1-6 alkyl or C1-6 alkoxy whicheach may be substituted with 1 or 2 substituents selected from a halogenatom, CF₃ and hydroxyl.

In the present invention, preferred rings as ring B are pyrrole,imidazole, pyridine, pyrimidine, pyridazine, triazine, azepine,diazepine, oxazine, oxazepine, thiazine and thiazepine. Particularlypreferred are pyridine, pyrimidine, pyridazine and triazine.

In the present invention, ring B is preferably a ring having nosubstituent other than R¹ and -Z-R², or a ring further substituted with1 or 2 substituents selected from the above substituent group 2. Ring Bis more preferably ring B having no further substituent, or ring Bfurther substituted with 1 or 2 substituents selected from C1-15 alkyl,C2-15 alkenyl or C2-15 alkynyl which each may be substituted, hydroxylwhich may be protected, cyclopropane, cyclobutane, cyclopentane,cyclohexane, phenyl, a halogen atom, CF₃ and cyano in the abovesubstituent group 2. Ring B is most preferably ring B having no furthersubstituent or ring B further substituted with one substituent selectedfrom C1-6 alkyl or C2-6 alkenyl which each may be substituted, hydroxylwhich may be protected with C1-6 alkyl which may be substituted,cyclopropane, cyclobutane, a halogen atom, CF₃ and cyano. In thisconnection, the substituent of the C1-6 alkyl, C2-6 alkenyl or C2-6alkynyl is preferably one substituent selected from C1-6 alkoxy, ahalogen atom, hydroxyl, CN and COOH.

In the present invention, Z or Z^(a) is preferably —NR³—, in which R³has the same meaning as described above, an oxygen atom, a sulfur atomwhich may be oxidized, —CR^(4a)R^(5a)—, in which R^(4a) and R^(5a) aretaken together to represent (i) oxo, (ii) C2-5 alkylene in which onecarbon atom may be substituted with one oxygen atom, nitrogen atom orsulfur atom which may be oxidized, the C2-5 alkylene being substitutedwith a substituent(s), or (iii) C1-6 alkylidene which may besubstituted. Z or Z^(a) is preferably —NR₃—, in which R³ has the samemeaning as described above, or —CR^(4b)R^(5b)R—, in which R^(4b) andR^(5b) are taken together to represent C2-5 alkylene in which one carbonatom may be substituted with one oxygen atom, nitrogen atom or sulfuratom which may be oxidized, the C2-5 alkylene being substituted with asubstituent(s), and most preferably —NR³—, in which R³ has the samemeaning as described above. Among these, —NR^(3a)—, in which R^(3a) is ahydrogen atom, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl orsubstituted C2-6 alkenyl, is particularly preferred.

In the present invention, when the ring represented by R² and R^(2a) isa bicyclic unsaturated carbocyclic ring or bicyclic unsaturatedheterocyclic ring containing benzene or a pyridine ring, the benzene orthe pyridine ring is bound to the group Z or Z^(a).

In the present invention, preferred compounds represented by formula (I)are those exemplified in the following Tables. TABLE 1 (I-B-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 2 (I-B-1)

No.

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

In the present invention, more preferred compounds are compounds offormula (I-A).

In the present invention, preferred compounds represented by formula(I-A) are those exemplified in the following Tables and followingExample compounds. TABLE 3 (I-A-1)

No.

1

2

3

4

5

6

7

8

9

TABLE 4 (I-A-2)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

In Tables 1 to 4, ring A is preferably unsubstituted or substituted with1 or 2 substituents selected from a halogen atom, CF₃, OCF₃, hydroxyl,mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo,and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6alkylthio which each may be substituted with 1 or 2 substituentsselected from a halogen atom, CF₃ and hydroxyl. Ring A is morepreferably unsubstituted ring A, or ring A substituted with 1 or 2substituents selected from a halogen atom, CF₃, hydroxyl, carboxyl,(C1-6 alkoxy)carbonyl, cyano, oxo, and C1-6 alkyl or C1-6 alkoxy whicheach may be substituted with 1 or 2 substituents selected from a halogenatom, CF₃ and hydroxyl.

In Tables 1 to 4, each ring represented by ring B may be substitutedwith 1 or 2 substituents selected from the above substituent group 2 onsubstitutable position(s). Among the substituent group 2, C1-15 alkyl,C2-15 alkenyl or C2-15 alkynyl which each may be substituted, hydroxylwhich may be protected, cyclopropane, cyclobutane, cyclopentane,cyclohexane, phenyl, a halogen atom, CF₃ and cyano are preferred. Ring Bis more preferably unsubstituted ring B, or ring B substituted with onesubstituent selected from C1-6 alkyl or C2-6 alkenyl which each may besubstituted, hydroxyl which may be protected with C1-6 alkyl which maybe substituted, cyclopropane, cyclobutane, a halogen atom, CF₃ andcyano.

R¹ is preferably (i) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl whicheach may be substituted, (ii) amino which may be protected, (iii)hydroxyl which may be protected, (iv) mercapto which may be protected,or (v) a cyclic group which may be substituted. When R¹ is a cyclicgroup which may be substituted and the cyclic group is a heterocyclicring containing a nitrogen atom, the nitrogen atom is preferably boundto ring B.

In the present invention, R¹ is more preferably amino which may beprotected. The amino which may be protected is preferably amino whichmay be protected with 1 or 2 of C1-15 alkyl which may be substituted,and more preferably amino substituted with one C1-15 branched orstraight alkyl which may be substituted, or amino substituted with twoC1-15 branched or straight alkyls which may be substituted. The C1-15branched or straight alkyl which may be substituted is preferablyunsubstituted C1-15 branched or straight alkyl, or C1-15 branched orstraight alkyl substituted with 1 or 2 substituents selected from ahalogen atom, CF₃, cyano, hydroxyl, C1-6 alkoxy, and C3-6 cycloalkylwhich may contain 1 or 2 hetero atoms selected from an oxygen atom, asulfur atom and a nitrogen atom.

R^(1a) is preferably (i) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynylwhich each may be substituted with the above substituent group 1, (ii)NR⁸R⁹, in which R⁸ and R⁹ have the same meanings as described above,(iii) OR¹⁰, in which R¹⁰ has the same meaning as described above. R^(1a)is more preferably NR⁸R⁹, in which R⁸ and R⁹ are each preferably (a) ahydrogen atom, or (b) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl whicheach may be substituted with the above substituent group 1.

NR⁸R⁹ is preferably NR^(8A)R^(9A), in which one of R^(8A) and R^(9A) isC1-15 alkyl which may be substituted with the substituent group 1, andanother is a hydrogen atom or C1-15 alkyl which may be substituted withthe above substituent group 1. More specifically, in NR^(8A)R^(9A),preferred are (1) a combination in which R^(8A) is a hydrogen atom, andR^(9A) is C1-15 branched or straight alkyl which may be substituted withthe above substituent group 1, and (2) a combination in which R^(8A) andR^(9A) are each C1-15 branched or straight alkyl which may besubstituted with the above substituent group 1. The C1-15 branched orstraight alkyl which may be substituted with the above substituent group1 is preferably unsubstituted C1-15 branched or straight alkyl, or C1-15branched or straight alkyl substituted with 1 or 2 substituents selectedfrom a halogen atom, CF₃, cyano, hydroxyl and C1-6 alkoxy.

R² is preferably a monocyclic or bicyclic unsaturated carbocyclic ringwhich may be substituted, or a monocyclic or bicyclic unsaturatedheterocyclic ring which may be substituted. R² is more preferably a ringrepresented by R^(2a), that is, (1) a monocyclic or bicyclic unsaturatedcarbocyclic ring which may be substituted, (2) pyridine which may besubstituted, (3) a bicyclic heterocyclic ring which may be substituted,in which benzene and a 5- or 6-membered monocyclic heterocyclic ring arefused, (4) a bicyclic heterocyclic ring which may be substituted, inwhich a pyridine ring and a C5-6 monocyclic carbocyclic ring are fused,or (5) a bicyclic heterocyclic ring which may be substituted, in which apyridine ring and a 5- or 6-membered monocyclic heterocyclic ring arefused. R^(2a) is preferably a benzene, indene, indane, naphthalene,tetrahydronaphthalene, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, pyridine or naphthyridine ring, whichmay be substituted, and more preferably a benzene, naphthalene,tetrahydronaphthalene or pyridine ring, which may be substituted. Inthis connection, in the case of the indene, indane andtetrahydronaphthalene rings, the benzene ring in these rings is bound toZ or Z^(a).

Also, the “substituent” substituted on the ring represented by R² andR^(2a) is preferably a substituent shown in the above substituent group7. The substituent is preferably (1) C1-15 alkyl which may besubstituted, (2) C1-15 alkenyl which may be substituted, (3) hydroxylwhich may be protected, (4) mercapto which may be protected, (5) aminowhich may be protected, (6) carbamoyl which may be protected, (7)carboxyl which may be protected, (8) sulfo which may be protected, (9)sulfino which may be protected, (10) cyano, (11) a halogen atom, (12) acyclic group which may be substituted, or (13) sulfino which may beprotected. The substituent is more preferably (1) C1-6 alkyl, (2) C2-6alkenyl, (3) unsubstituted hydroxyl, or hydroxyl protected with C1-6alkyl which may be substituted or a protecting group having leavingability (among these, particularly C1-6 alkoxy and trifluoromethoxybeing preferred), (4) carboxyl, or carboxyl protected with C1-6 alkyl orbenzyl, (5) cyano, (6) a halogen atom, or (7) a cyclic group which maybe substituted. These substituents may be substituted on 1 to 5substitutable positions on the ring represented by R² and R^(2a), and 1,2 or 3 substitution is particularly preferred. Particularly, when R² andR^(2a) are a 6-membered monocyclic ring, specifically benzene or apyridine ring, substitution at (1) 2-position, (2) 3-position, (3)4-position, (4) 2- and 4-positions, or (5) 2-, 4- and 6-positions ispreferred.

R³ is preferably a hydrogen atom, C1-6 alkyl which may be substituted(for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl or hexyl, which each may be substituted),or C2-6 alkenyl which may be substituted (for example, vinyl, propenyl,butenyl, pentenyl or hexenyl, which each may be substituted).

Among the compounds represented by formulae (I-A-1) and (I-A-2),

wherein ring A is unsubstituted, or substituted with 1 or 2 substituentsselected from a halogen atom, CF₃, hydroxyl, carboxyl, (C1-6alkoxy)carbonyl, cyano, oxo, and C1-6 alkyl or C1-6 alkoxy which eachmay be substituted with 1 or 2 substituents selected from a halogenatom, CF₃ and hydroxyl;

ring B is unsubstituted, or substituted with a substituent selected fromC1-15 alkyl which may be substituted, C2-15 alkenyl, hydroxyl which maybe protected, cyclopropane, cyclobutane, a halogen atom, CF₃ and cyanoon substitutable position(s).

Also, the compound represented by formula (I-A) is more preferably acompound represented by formula (I-A-3):

R^(1A) represents amino which may be protected with 1 or 2 of C1-15alkyl which may be substituted; G^(a1)s each independently represents ahydrogen atom, a halogen atom, CF₃, OCF₃, hydroxyl, mercapto, carboxyl,(C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, or C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may besubstituted with 1 or 2 substituents selected from a halogen atom, CF₃and hydroxyl; G² represents a hydrogen atom, C1-15 alkyl, C2-15 alkenylor C2-15 alkynyl which may be substituted, hydroxyl which may beprotected, cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl,a halogen atom, CF₃, or cyano, and other symbols have the same meaningsas described above or

a compound represented by formula (I-A-4):

wherein R^(1aA) represents NR^(8A)R^(9A), in which one of R^(8A) andR^(9A) represents C1-15 alkyl which may be substituted with the abovesubstituent group 1, and another is a hydrogen atom or C1-15 alkyl whichmay be substituted with the above substituent group 1; G^(a2)s eachindependently represents a hydrogen atom, a halogen atom, CF₃, OCF₃,hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro,cyano, oxo, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy orC1-6 alkylthio which each may be substituted with 1 or 2 substituentsselected from a halogen atom, CF₃ and hydroxyl; and other symbols havethe same meanings as described above.

In the present invention, specific compounds are following compoundsdescribed in Examples. Preferable compounds are

(1)N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(2)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(3)N⁵-(2-chloro-4-methoxyphenyl)-6-ethyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(4)N²-(2-chloro-4-methoxyphenyl)-N²-ethyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,

(5)N⁵-(2-chloro-4-methoxyphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(6)N²-aryl-N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,

(7)6-methyl-N⁵-[2-methyl-4-(trifluoromethoxy)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(8)N⁷-butyl-N⁵-(2-chloro-4-methoxyphenyl)-N⁷-ethyl-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(9)N⁵-(2-ethyl-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,

(10)6-methoxy-N⁵-(4-methyl-2-vinylphenyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,or

(11)N⁵-(2-ethyl-4-methylphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylene, alkenylene and alkynyl include straight and branched isomers.Isomers based on double bond, ring, fused ring (E, Z, cis, trans),isomers resulting from the presence of asymmetric carbon(s)(R-configuration, S-configuration, α-configuration, β-configuration,enantiomers, diastereoisomers), optically active compounds havingoptical rotation (D, L, d, l-configuration), polar compounds obtained bychromatographic separations (highly polar compound, less polarcompound), equilibrium compounds, rotational isomers, the mixtures areexisted by free ratio, racemic mixtures are included in the presentinvention.

In the present invention, as is apparent to one skilled in the art,unless otherwise indicated,

the mark

shows that the bond is on the other side of paper (α-configuration),

the mark

shows that the bond is in front of paper (β-configuration),

the mark

shows that the bond is α-configuration or β-configuration, and

the mark

shows that the bond is a mixture of α-configuration and β-configuration.

The compound of the present invention of formula (I) may be convertedinto a non-toxic salt or a corresponding pharmaceutically acceptablesalt by known methods. In the present invention, non-toxic salts orpharmaceutically acceptable salts are included. As pharmaceuticallyacceptable salts are non-toxic and water-soluble salts are preferable.

Appropriate salts are, salts of alkali metals, such as potassium,sodium, lithium; salts of alkaline-earth metals, such as calcium,magnesium; ammonium salts, such as tetramethylammonium,tetrabutylammonium; salts of organic amines, such as triethylamine,methylamine, dimethylamine, cyclopentylamine, benzylamine,phenethylamine, piperidine, monoethanolamine, diethanolamine,tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine,acid addition salts, for example, inorganic acids, such ashydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate;salts of organic acid, such as acetate, trifluoroacetate, lactate,tartrate, oxalate, fumarate, maleate, benzoate, citrate,methanesulphonate, ethanesulphonate, benzenesulphonate,toluenesulphonate, isethionate, glucuronate, gluconate.

N-oxides are the compounds where nitrogen of the compound of formula (I)and formula (I-A) is oxidized. The present compound may be convertedinto an N-oxide compound by any known methods.

Besides, in the present invention, solvates of the compound of formula(I), solvates of the above-described a non-toxic salt or a correspondingpharmaceutically acceptable salt of formula (I) and solvates of theabove-described an N-oxide compound of formula (I) are included. Thesolvates are preferably non-toxic and water-soluble. The appropriatesolvates include, for example, solvates such as water, alcohol solvents(ethanol, etc.), and the like.

The prodrug for the compound of formula (I) or formula (I-A) means acompound which is converted to the compound of formula (I) or formula(I-A) by reaction with an enzyme, a gastric acid, or the like, in theliving body. Examples of the prodrug for the compound of formula (I) orformula (I-A) include a compound wherein amino of the compound offormula (I) or formula (I-A) is substituted with acyl, alkyl, phosphoricacid, or the like (e.g., a compound wherein amino of the compound offormula (I) or formula (I-A) is substituted with eicosanyl, alanyl,pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl,tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethy,tert-butyl, etc.); a compound wherein hydroxyl of the compound offormula (I) or formula (I-A) is substituted with acyl, alkyl, phosphoricacid, boric acid, or the like (e.g., a compound wherein hydroxyl of thecompound of formula (I) or formula (I-A) is modified with acetyl,palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl,dimethylaminomethylcarbonyl, etc.); a compound wherein carboxyl of thecompound of formula (I) or formula (I-A) is modified with ester, amide,or the like (e.g., a compound wherein carboxyl of the compound offormula (I) or formula (I-A) is modified with ethyl ester, isopropylester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester,pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester,cyclohexyloxycarbonylethyl ester, methyl amide, etc.), and the like. acompound wherein carboxyl of the compound of formula (I) or formula(I-A) is modified hydroxymethyl. These compounds may be prepared by perse known method. In addition, the prodrug for the compound of formula(I) or formula (I-A) may hydrate or non-hydrate.

PRODUCTION PROCESS OF THE COMPOUND OF THE PRESENT INVENTION

The compound of the present invention can be produced, for example, bythe following processes.

A compound represented by formula (I):

wherein all symbols have the same meanings as described above,

can be produced by reacting a compound represented by formula (II):

wherein Y represents a leaving group (for example, a halogen atom,mesyl, tosyl, mesyloxy, tosyloxy, trifluoromethansulfonyloxy,methylthio),

with a compound represented by formula (III):H-Z-R²   (II)

wherein all symbols have the same meanings as described above.

The above reaction is known, and is carried out, for example, by heatingat 50° C. to 250° C. in an organic solvent (for example,N-methylpyrrolidone, dimethylformamide, isopropanol) or without solvent.The heating is carried out by water bath, oil bath, sand bath ormicrowave.

Also, the compound can be produced by reacting a compound represented byformula (II) with a compound represented by formula (III-1):H₂N—R²   (III-1)

wherein R² has the same meaning as described above,

to obtain a compound represented by formula (I-1):

wherein all symbols have the same meanings as described above,

followed by N-alkylation reaction.

The reaction of the compound represented by formula (II) with thecompound represented by formula (III-1) is carried out in the samemanner as in the above reaction of the compound represented by formula(II) with the compound represented by formula (III).

The N-alkylation reaction is known and is carried out, for example, byusing a corresponding alkyl halide (for example, methyl iodide) at 0 to40° C. in the presence of a base (for example, sodium hydride) in anorganic solvent (for example, dimethylformamide, dimethylacetamide,1,3-dimethyl-2-imidazolidinone, tetrahydrofuran).

Also, a compound in which the ring

is a [1,2,5]thiadiazol[3,4-d]pyrimidine in the compounds represented byformula (I), can be produced by reacting a compound represented byformula (IV):

wherein all symbols have the same meanings as described above,

with thionyl chloride or thionylaniline.

The above reaction is known and is carried out, for example, at 50 to120° C. in an organic solvent or without solvent.

Furthermore, the compound represented by formula (I) can be produced byreacting a compound represented by formula (XI):

wherein all symbols have the same meanings as described above,

with a compound represented by formula (VI)H—R¹   (VI)

wherein R¹ has the same meaning as described above.

This reaction is known and is carried out, for example, at roomtemperature to reflux temperature in the presence of a tertiary amine(for example, triethylamine, diisopropylethylamine) in an organicsolvent (for example, tetrahydrofuran, isopropanol) or at roomtemperature to reflux temperature without solvent.

Moreover, the compound represented by formula (I) in which Z is —CO— canbe produced by reacting a compound represented by formula (XII):

wherein E represents C1-4 alkyl, and other symbols have the samemeanings as described above,

with a compound represented by formula (XIII):M-R²   (XIII)

wherein M is magnesium-Y^(a), in which Y^(a) represents a halogen atom,or lithium; and R² has the same meaning as described above.

The reaction is known and is carried out, for example, at −40° C. to 0°C. in an organic solvent (for example, tetrahydrofuran, diethyl ether).Additionally, the compound represented by formula (XIII) is produced,for example, by reacting a compound represented by formula (XIV):Y^(a)—R²   (XIV)

wherein all symbols have the same meanings as described above,

with a Grignard reagent (for example, methyl magnesium bromide,isopropyl magnesium bromide, phenyl magnesium bromide, butyl lithium,phenyl lithium, or the like) or an alkyl lithium reagent (for example,butyl lithium, sec-butyl lithium, tert-butyl lithium, or the like).

The compound represented by formula (II) can be produced, for example,by a method shown in the following reaction scheme A, wherein allsymbols have the same meanings as described above:

The compound represented by formula (IV) can be produced, for example,by a method shown in the following reaction scheme B, wherein allsymbols have the same meanings as described above:

The compounds represented by formulae (V) and (X) per se are known orcan be produced by known methods. For example,2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine is described in J.Amer. Chem. Soc., 81, 3118-3111 (1959).

Also, 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine can beproduced, for example, by a method shown in the following reactionscheme C:

Furthermore, 2-ethylthiothieno[3,2-d]pyrimidin-4-on can be produced bythe method described in JP-A-3-17083, and2-ethylthiothieno[2,3-d]pyrimidin-4-on can be produced by the methoddescribed in U.S. Pat. No. 4,146,716.

Moreover, 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine,5,7-dichloropyrazolo[1,5-a]pyrimidine,5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine,5,7-dichloroimidazo[1,2-a]pyrimidine, and5,7-dichloro-6-methylimidazo[1,2-a]pyrimidine can be respectivelyproduced by the methods described in Examples later.

The compound represented by formula (XI) can be produced by reacting thecompound represented by formula (V) with the compound represented byformula (III). Also, it can be produced by the method described inExample later.

The compound represented by formula (XII) can be produced, for example,by a method described in the following reaction scheme D, wherein allsymbols have the same meanings as described above:

Also, in the present invention, other stating materials and each reagentper se are known or can be produced by known methods.

In each reaction in the present specification, reaction products can bepurified by a usual purification means, for example, distillation undernormal pressure or reduced pressure distillation, high-performanceliquid chromatography using silica gel or magnesium silicate, thin-layerchromatography, column chromatography, washing, recrystallization or thelike. The purification may be carried out after each reaction stage orafter some reaction stages.

And the starting materials and reagents in the present invention may beknown per se or may be prepared by known methods.

In each reaction in the present specification, reaction products may bepurified by conventional purification techniques, e.g. by distillationunder atmospheric or reduced pressure, by high performance liquidchromatography, by thin layer chromatography or by column chromatographyusing silica gel or magnesium silicate; or by washing or byrecrystallization. Purification may be carried out after each reactionor after a series of reactions.

Toxicity

The toxicity of the compounds of formula (I) and formula (I-A) of thepresent invention is very low and therefore, it is confirmed that thesecompounds are safe for use as medicine.

Application to Pharmaceuticals

The compounds of the present invention of the formula (I) and formula(I-A) are useful, in order to possess CRF receptor binding activity andantagonistic activity, for the prevention and/or treatment of CRFmediated diseases, for example, psychiatric and neurologic disorders,digestive diseases, pulmonary disorders, endocrine disorders, metabolicdisorders, cardiovascular disorders, dermatologic disorders,genitourinary disorders, ophthalmologic disorders or musculoskeletaldisorders.

In particular, as psychiatric and neurologic disorders, for example,mood disorders such as depression, single episode depression, recurrentdepression, postpartum depression, child abuse induced depression,bipolar disorder, premenstrual dysphoric disorder, dysphoric disorder inaround the time of climacteric, perimenopausal dysphoric disorder;anxiety disorders such as generalized anxiety disorder, panic disorder,obsessive compulsive disorder, phobic disorders such as acrophobia,claustrophobia, agoraphobia, social phobia; adjustment disorders such asemotional injury, conduct disorder or disorder with both, physicalcomplaint, isolating oneself from society, occupational stagnant,stagnant academic achievement; stress-related disorders such asposttraumatic stress disorder (PTSD), stress induced immunosuppression,stress induced headache, stress induced fever, stress induced pain, postoperative stress, stress induced gastrointestinal disorder, irritablebowel syndrome; eating disorders such as anorexia nervosa, binge eatingdisorder, nervous vomiting; symptom caused by psychotropic substance ordependency thereon such as alcoholic withdrawal symptoms, alcoholdependence, drug addiction, drug dependency; organic mental disordersuch as senile dementia of Alzheimer's type, multi-infarct dementia;schizophrenic disorder; attention-deficit hyperactivity disorder;neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis; pain;convulsive disorders such as convulsion, muscle spasm; episodic diseasessuch as epilepsy, attack, migraine; or sleep disorders such asnonorganic sleep disorder, fiber myalgic sleep disorder are given. Asdigestive diseases, for example, peptic ulcer; inflammatory boweldisease such as ulcerative colitis, Crohn's disease; irritable bowelsyndrome; gastrointestinal disorder; diarrhea; constipation are given.As pulmonary disorders, for example, asthma, bronchitis, chronicobstructive pulmonary disease, allergic rhinitis is given. As endocrinedisorders, for example, disturbed thyroid function, Cushing's disease orsyndrome of inappropriate antidiuretic hormone secretion is given. Asmetabolic disorders, for example, obesity or hypoglycemia is given. Ascardiovascular disorders, for example, hypertension, ischemic heartdisease or cerebral vascular disease is given. As dermatologicdisorders, for example, atopic dermatitis, allergic contact dermatitisor psoriasis is given. As genitourinary disorders, for example, urinarydisturbance, pollakiuria or urinary incontinence is given. Asophthalmologic disorders, for example, uveitis is given. Asmusculoskeletal disorders, for example, chronic rheumatoid arthritis,osteoarthrosis or osteoporosis are given.

A combination agent obtained by combining the compound of formula (I) orformula (I-A) with other medicaments may be administered to accomplishthe following purposes (1) to supplement and/or enhance the preventiveand/or therapeutic effect of the present compound; (2) to improve thekinetics and/or absorption and reduce the dose of the present compound;and/or (3) to eliminate the side effects of the present compound.

A combination of the compound of formula (I) or formula (I-A) or a saltthereof, a solvate thereof or a prodrug thereof and other medicamentsmay be administered in the form of the formulations having thesecomponents incorporated in one preparation, or may be administered inseparate preparations. In the case where these medicaments areadministered in separate preparations, they may be administeredsimultaneously or at different times. In the latter case, the compoundof formula (I) or formula (I-A) or a salt thereof, a solvate thereof ora prodrug thereof may be administered before the other medicaments.Alternatively, the other medicaments may be administered before thecompound of formula (I) or formula (I-A) or a salt thereof, a solvatethereof or a prodrug thereof. The method for the administration of thesemedicaments are the same or different.

The diseases on which the preventive and/or therapeutic effect of theabove mentioned combination preparations works are not specificallylimited but may be those for which the preventive and/or therapeuticeffect of the compound represented by formula (I) or formula (I-A) or asalt thereof, a solvate thereof or a prodrug thereof or othermedicaments is supplemented and/or enhanced.

The weight ratio of the compound of formula (I) or formula (I-A) or asalt thereof, a solvate thereof or a prodrug thereof and the othermedicaments is not specifically limited.

The other medicaments are not limited to low molecular compound, may bemacromolecular protein, polypeptide and polynucleotide (DNA, RNA, gene),antisense, decoy, antibody or vaccine etc. The dosage of othermedicaments can be properly selected based on the dosage which can foron clinical it.

The weight ratio of the compound of formula (I) or formula (I-A) or asalt thereof, a solvate thereof or a prodrug thereof and the othermedicaments is not specifically limited, and may be properly selecteddepending upon, for example, ages, body weights, the route ofadministration, the duration of the treatment, target disease, symptoms,the combination, etc. For example, the other medicaments may be used0.01-100 percent by weight for the compound of formula (I) or a saltthereof, a solvate thereof or a prodrug thereof The other medicamentsmay be administered as the combination of one or more selected fromfollowing homogeneous groups and the different kind groups by arbitraryrate.

As the other medicaments of a combination of the compound of formula (I)or formula (I-A)- or a salt thereof, a solvate thereof or a prodrugthereof, there are as follows. And if it is a compound that has theaction similar to the action mechanism of the medicaments, not only theone found by present but also the one that will be found in the futureis included.

Examples of other medicaments for supplementing and/or enhancing thepreventive and/or therapeutic effect of the compound (I) or formula(I-A) on mood disorders include antidepressant, such as a tricyclicantidepressant, a tetracyclic antidepressant, a monoamine oxidase (MAO)inhibitor, a serotonin and noradrenaline reuptake inhibitor (SNRI), aselective serotonin reuptake inhibitor (SSRI), a serotonin reuptakeinhibitor; a psychoanaleptic, an antianxiety agent, an antipsychoticagent, a mitochondrial benzodiazepine receptor (MBR) ligand, an NK1antagonist, and the like.

Examples of other medicaments for supplementing and/or enhancing thepreventive and/or therapeutic effect of the compound (I) or formula(I-A) on anxiety disorders include an antianxiety agent, such as abenzodiazepine anxiolytic, a thienodiazepine anxiolytic, anon-benzodiazepine anxiolytic, a MBR ligand, and the like.

Examples of other medicaments for supplementing and/or enhancing thepreventive and/or therapeutic effect of the compound (I) or formula(I-A) on irritable bowel syndrome include a gastrointestinal promotilityagent, a 5-HT₃ antagonist, a 5-HT₄ agonist, an anticholinergic agent, anantidiarrheal drug, a lapactic, an autonomic modulating agent, anantidepressant, an antianxiety agent, and the like.

As an antidepressant, for example, a tricyclic antidepressant, such asamitriptyline hydrochloride, imipramine hydrochloride, clomipraminehydrochloride, dosulepin hydrochloride, nortriptyline hydrochloride,lofepramine hydrochloride, trimipramine maleate, amoxapine; atetracyclic antidepressant, such as maprotiline hydrochloride, mianserinhydrochloride, setiptiline maleate; a MAO inhibitor, such as safrazinehydrochloride; SNRI, such as milnacipran hydrochloride, venlafaxinehydrochloride; SSRI, such as fluvoxamine maleate, paroxetinehydrochloride, fluoxetine hydrochloride, citalopram hydrochloride; aserotonin reuptake inhibitor, such as trazodone hydrochloride are given.

As an antianxiety agent, for example, a benzodiazepine anxiolytic, suchas alprazolam, oxazepam, oxazolam, cloxazolam, clorazepate dipotassium,chlordiazepoxide, diazepam, tofisopam, triazolam, prazepam, fludiazepam,flutazolam, flutoprazepam, bromazepam, mexazolam, medazepam, ethylloflazepate, lorazepam; a thienodiazepine anxiolytic, such as etizolam,clotiazepam; a non-benzodiazepine anxiolytic, such as tandospironecitrate and hydroxylzine hydrochloride are given.

As a psychoanaleptic, for example, methylphenidate hydrochloride andpemoline are given.

As an antipsychotic agent, for example, sulpiride, trazodonehydrochloride, serotonin-dopamine antagonist such as risperidone,perospirone hydrochloride hydrate, quetiapine fumarate and olanzapineare given.

As a gastrointestinal promotility agent, for example, trimebutinemaleate and polycarbophil calcium are given.

As a 5-HT₃ antagonist, for example, alosetron is given.

As a 5-HT₄ agonist, for example, tegaserod, cisapride and mosapridecitrate are given.

The weight ratio of the compound (I) or formula (I-A) and the othermedicaments is not specifically limited.

Any combination of two or more other medicaments may be administered.

Furthermore, the other medicaments for supplementing and/or enhancingthe preventive and/or therapeutic effect of the compound (I) or formula(I-A) include not only those found so far but also those which will befound on the basis of the above mentioned mechanism.

For the purpose above described, the compounds of formula (I) or formula(I-A), a non-toxic salt thereof, or a combination of the compounds offormula (I) and other medicaments may be normally administeredsystemically or locally, usually by oral or parenteral administration.

The doses to be administered are determined depending upon, for example,ages, body weights, symptoms, the desired therapeutic effects, the routeof administration and the duration of the treatment. For the humanadult, the doses per person are generally from 1 mg to 1000 mg, by oraladministration, up to several times per day, and from 0.1 mg to 100 mg,by parenteral administration, up to several times per day, or continuousadministration 1 to 24 hours per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

To administer the compounds in the present invention of formula (I), useis made of solid preparations for internal use and liquid preparationsfor internal use for oral administration as well as preparations forinjections, external preparations, suppositories, eye drops, nasaldrops, inhalations and the like for parenteral administration.

Examples of the solid preparations for internal use for oraladministration include tablets, pills, capsules, powders, granules andthe like. The capsules include hard capsules and soft capsules. Thetablets include sublingual tablet, oral patch and orally disintegratingtablet.

Such a solid preparation for internal use is prepared by a formulationmethod commonly employed by using an active substances withoutmodification, or a mixture of one or more active substances with anexcipient (lactose, mannitol, glucose, microcrystalline cellulose,starch, etc.), a binder (hydroxypropylcellulose, polyvinylpyrrolidone,magnesium metasilicate aluminate, etc.), a disintegrating agent (calciumcellulose glycolate, etc.), a lubricant (magnesium stearate, etc.), astabilizer, a solubilizing agent (glutamic acid, aspartic acid, etc.).If necessary, it may be coated with a coating agent (sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.).It may be coated with two or more layers. Moreover, capsules made of anabsorbable material such as gelatin are involved in the scope thereof.

The liquid preparations for internal use for oral administration includepharmaceutically acceptable aqueous solutions, suspensions, emulsions,syrups, elixirs and the like. Such a liquid preparation is prepared bydissolving, suspending or emulsifying one or more active substances in adiluent commonly employed (purified water, ethanol or a mixture thereof,etc.). Such liquid forms may also further comprise some additives suchas humectants, suspending agents, emulsifying agents, sweetening agents,flavoring agents, aroma, preservatives, buffers and the like.

The external preparations for parenteral administration includeointments, gels, creams, fomentations, patches, liniments, atomizedagents, inhalations, sprays, eye drops and nasal drops and the like.Such a preparation contains one or more active substances and isprepared by a well known method or a commonly employed formulation.

Atomized agents, inhalations and sprays may contain, in addition to adiluent commonly employed, a stabilizer such as sodium hydrogen sulfite,a buffering agent for imparting isotonicity, for example, an isotonicagent such as sodium chloride, sodium citrate or citric acid. Theinhalations for parenteral administration include aerosols, powders forinhalation and liquids for inhalation. Such liquids for inhalations maybe dissolved or suspended in water or another adequate medium for use.The inhalations may be prepared in accordance with a well known method.For example, liquid preparations for inhalation may be, if necessary,prepared by appropriately selecting a preservative (benzalkoniumchloride, paraben, etc.), a colorant, a buffering agent (sodiumphosphate, sodium acetate, etc.), an isotonic agent (sodium chloride,concentrated glycerin, etc.), a thickener (carboxyvinyl polymer, etc.),an absorption promoter, and the like.

Powders for inhalation may be prepared, if necessary, by appropriatelyselecting a lubricant (stearic acid and its salt, etc.), a binder(starch, dextrin, etc.), an excipient (lactose, cellulose, etc.), acolorant, a preservative (benzalkonium chloride, paraben, etc.), anabsorption promoter, and the like.

When the liquids for inhalation are administered, a sprayer (atomizer,nebulizer) is usually used. When the powders for inhalation are used, aninhalation administration apparatus for powder agents is usually used.

Methods for producing a spray are described in detail in, for example,U.S. Pat. No. 2,868,691 and U.S. Pat. No. 3,095,355.

The injections for parenteral administration include solutions,suspensions, emulsions and solid injections to be dissolved or suspendedbefore use. Such an injection is used by dissolving, suspending oremulsifying one or more active substances in a solvent. The solventincludes, for example, distilled water for injection, physiologicalsaline, vegetable oils, alcohols such as propylene glycol, polyethyleneglycol and ethanol, and mixtures thereof The injection may furthercontain a stabilizer, a dissolution aid (glutamic acid, aspartic acid,Polysorbate 80 (registered trademark), etc.), a suspending agent, anemulsifier, a soothing agent, a buffer, a preservative, and the like.Such an injection may be produced by sterilizing at the final step oremploying an aseptic process. Alternatively, it is also possible that anaseptic solid product such as a freeze-dried product is produced andsterilized or dissolved in aseptic distilled water for injection oranother solvent before use.

Other compositions for parenteral administration include suppositoriesand pessaries for vaginal administration which contain one or moreactive substances, and are prepared in accordance with commonformulations.

EFFECT OF THE INVENTION

The compounds of the present invention possess CRF receptor bindingactivity and potent antagonistic activity.

BEST MODE FOR CARRYING OUT THE INVENTION

Now, the present invention is described in greater detail by referenceto the following Examples, although the present invention is notconstrued as being restricted thereto.

Solvents given in parentheses concerning chromatographic separation andTLC indicate each the elution solvent or the developing solvent employedand the ratio is expressed in ratio by volume.

Solvents given in parentheses concerning NMR indicate each the solventemployed in measurement.

The name of the compounds used in the present specification isdesignated according to ACD/Name™ (version 6.00, Advanced ChemistryDevelopment Inc.).

EXAMPLE 1 5,7-dihydrofuro[3,4-d]pyrimidine-2,4(1H,3H)-dione

To Methyl 4-oxotetrahydrofuran-3-carboxylate (18.30 g), urea (11.44 g),methanol (100 mL) and concentrated hydrochloric acid (5 mL) were added.The mixture was refluxed with heating for two hours. The obtainedsuspension was stirred for 15 minutes in an ice-bath. The precipitatewas filtered under reduced pressure, and washed with water (20 mL×2times). 2 mol/L aqueous solution of sodium hydroxide (100 mL) and water(30 mL) were added to the obtained precipitate. The mixture was refluxedwith heating for 1 hour. Concentrated hydrochloric acid was dropped tothe reaction solution in an ice-bath. The precipitate was filtered underreduced pressure, and then the precipitate was washed with water andacetone, dried under reduced pressure to give the title compound (15.7g) having the following physical data.

TLC: Rf 0.32 (methanol:ethyl acetate=10:1);

¹H-NMR(300 MHz, DMSO-d₆): δ 11.23, 11.44-11.10, 11.00, 4.70.

EXAMPLE 2 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine

Under argon gas atmosphere, phenylphosphonic dichloride (16.1 mL) wasadded to the compound prepared in Example 1 (15.7 g). The mixture wasstirred for 6 hours at 135° C., and then for 30 minutes at 165° C. Afterthe reaction mixture was cooled, it was dropped into ice-water (100 mL).Ethyl acetate (100 mL) was added to the mixture solution. An insolublematter was removed by filtration under reduced pressure, and was washedwith ethyl acetate. The filtrate and the washings were combined, andthen the mixture was shaken and separated. The organic layer was washedwith a saturated sodium bicarbonate and a saturated sodium chloride,successively, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure, and then dried under vacuum to give the titlecompound (3.66 g) having the following physical data.

TLC: Rf 0.60 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 5.17, 5.09.

EXAMPLE 32-chloro-4-N,N-di-n-propylamino-5,7-dihydrofuro[3,4-d]pyrimidine

Under argon gas atmosphere, tetrahydrofuran (4 mL) was added to thecompound prepared in Example 2 (757 mg), and then the mixture wasstirred in an ice-bath. To the mixture, triethylamine (1.4 mL) anddi-n-propylamine (1.3 mL) were dropped. The mixture was stirred for 4hours at room temperature. The reaction mixture was poured into cooled10% aqueous solution of citric acid, and then the mixture was extractedby ethyl acetate. The extract was washed with a saturated aqueoussolution of sodium bicarbonate, and a saturated aqueous solution ofsodium chloride, successively, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=9:1 ) togive the title compound (784 mg) having the following physical data.

TLC: Rf 0.71 (n-hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 5.19, 4.86, 3.32, 1.62, 0.94.

EXAMPLE 4N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

A mixture of the compound prepared in Example 3 (300 mg) and2-chloro-4-methoxyaniline (554 mg) was reacted for 60 minutes bymicrowave (90 watt, 120° C.). The reaction mixture was cooled to roomtemperature, and poured into a mixed solution of ethyl acetate/asaturated aqueous solution sodium bicarbonate and then the mixture wasextracted by ethyl acetate. The extract was washed with water and asaturated aqueous solution of sodium chloride, dried over magnesiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by column chromatography on silica gel (toluene:ethylacetate=20:1→hexane:ethyl acetate=8:1→6:1) to give the title compound(385 mg) as a pale yellow powder having the following physical data.

TLC: Rf 0.29 (hexane:ethyl acetate=4:1);

¹H-NMR(300 MHz, CDCl₃): δ 0.93, 1.59, 3.30, 3.79, 4.82, 5.18, 6.81,6.94, 7.03, 8.28.

EXAMPLE 4 (1)-4(21)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 4 using a corresponding compound.

EXAMPLE 4(1)N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.18 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.92, 1.63, 2.00, 2.74, 2.97, 3.43, 3.78,6.79, 6.93, 6.98, 8.34.

EXAMPLE 4(2)N²-(2-chloro-4-methoxyphenyl)-N⁴-(1-ethylpropyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.23 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.94, 1.58, 2.08, 2.59, 2.80, 3.78, 4.02,6.81, 6.93, 7.07, 8.46.

EXAMPLE 4(3)N²-(5,7-dimethyl-2,1,3-benzothiazol-4-yl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.21 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 0.64, 1.31, 1.99, 2.41, 2.68, 2.73, 2.91,3.14, 6.68, 7.28.

EXAMPLE 4(4)N²-(5,7-dimethyl-2,1,3-benzothiazol-4-yl)-N⁴-(1-ethylpropyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.18 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 0.75, 1.37, 2.06, 2.40, 2.55 2.68, 2.76,3.68, 3.92, 6.87, 7.28.

EXAMPLE 4(5)N²-(2-chloro-4-methoxyphenyl)-N⁴-(1-ethylpropyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

TLC: Rf 0.15 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.94, 1.58, 3.79, 4.03, 4.85, 4.98, 6.82,6.94, 7.10, 8.33.

EXAMPLE 4(6)N²-(5,7-dimethyl-2,1,3-benzothiazol-4-yl)-N⁴,N⁴-dipropyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

TLC: Rf 0.30 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.69, 1.37, 2.41, 2.69, 3.05, 4.79, 5.14,6.75, 7.29.

EXAMPLE 4(7)N²-(5,7-dimethyl-2,1,3-benzothiazol-4-yl)-N⁴-(1-ethylpropyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

TLC: Rf 0.28 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.80, 1.40, 2.40, 2.69, 3.60, 4.00, 4.80,4.94, 6.97, 7.29.

EXAMPLE 4(8)N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.48(hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.48, 2.35, 3.35, 3.81, 6.23, 6.91,6.98, 7.86, 8.62.

EXAMPLE 4(9)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.38 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.98, 1.66, 2.30, 3.72, 3.80, 5.78, 6.16,6.74, 6.90, 6.97, 7.81, 8.50.

EXAMPLE 4(10)N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷,N⁷-dipropyl[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.14 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.85, 1.49, 2.33, 3.37, 3.80, 6.89, 6.97,7.11, 8.12, 8.78.

EXAMPLE 4(11)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.24 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.97, 1.66, 3.29, 3.82, 5.29, 5.98, 6.13,6.51, 6.87, 6.99, 7.83, 7.93.

EXAMPLE 4(12)N⁵-(2-chloro-4-methoxyphenyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.30 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.90, 1.64, 3.58, 3.81, 5.36, 6.13, 6.48,6.86, 6.99, 7.84, 7.94.

EXAMPLE 4(13)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)-6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.21 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.97, 1.65, 2.29, 3.79, 3.85, 5.33, 6.87,6.95, 8.07, 8.67.

EXAMPLE 4(14)N⁵-(2-chloro-4-methoxyphenyl)-N⁷,N⁷-dipropyl[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.16 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.92, 1.69, 3.64, 3.82, 5.33, 6.66, 6.86,7.00, 7.94, 8.07.

EXAMPLE 4(15)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.14 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.97, 1.67, 3.29, 3.82, 5.35, 5.71, 6.73,6.87, 7.00, 7.97, 8.10.

EXAMPLE 4(16)N⁷-(2-chloro-4-methoxyphenyl)-N⁵-(1-ethylpropyl)imidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.15 (ethyl acetate:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.97, 1.70, 3.27, 3.81, 4.42, 5.33, 6.72,6.84, 6.97, 7.13, 7.43, 8.17.

EXAMPLE 4(17)N⁷-(2-chloro-4-methoxyphenyl)-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.50 (ethyl acetate:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.91, 1.64, 3.18, 3.81, 5.65, 6.73, 6.86,6.97, 7.21, 7.42, 8.32.

EXAMPLE 4(18)N⁷-(2-chloro-4-methoxyphenyl)-N⁵-(1-ethylpropyl)-6-methylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.32 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.98, 1.58, 2.23, 3.51, 3.65, 3.78, 6.86,6.92, 6.94, 7.26, 7.40, 8.87.

EXAMPLE 4(19)

N⁷-(2-chloro-4-methoxyphenyl)-6-methyl-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.42 (methylene chloride:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.52, 2.29, 3.18, 3.81, 6.90, 6.96,7.03, 7.27, 7.40, 8.95.

EXAMPLE 4(20)N²-(2,4-dichlorophenyl)-3-methyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2,4-diamine

TLC: Rf 0.57 (hexane:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.35, 7.34, 7.17, 6.70, 3.00, 2.92-2.83,2.20, 2.06, 1.43, 0.84.

EXAMPLE 4(21)N²-(2,4-dichlorophenyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.15 (benzene:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.56, 7.34, 7.23, 7.17, 3.46, 2.98, 2.76,2.01, 1.72-1.57, 0.94.

EXAMPLE 5N²-(2-chloro-4-methoxyphenyl)-N²-methyl-N⁴,N⁴-dipropyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

Under argon gas atmosphere, to a solution of the compound prepared inExample 4 (225 mg) in N,N-dimethylformamide (6 mL), sodium hydride (60%in oil suspension, 36 mg) and methyl iodide (0.075 mL), successively,were added in an ice-bath. The mixture was stirred for 1 hour at roomtemperature. To the reaction mixture, a saturated aqueous solution ofammonium chloride was added, and then the mixture was extracted withhexane/ethyl acetate (1/1). The organic layer was washed with water anda saturated aqueous solution of sodium chloride, successively, driedover magnesium sulfate and concentrated under reduced pressure. Theobtained residue was purified by column chromatography on silica gel(hexane:ethyl acetate=8:1→4:1) to give the title compound (224 mg) as apale yellow powder having the following physical data.

TLC: Rf 0.30 (hexane:ethyl acetate-4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.74, 1.42, 3.04, 3.37, 3.81, 4.80, 5.13,6.82, 6.99, 7.18.

EXAMPLE 5(1)-5(9)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 5 using a compound prepared in Example 4(1),4(3), 4(7), 4(8), 4(10), 4(12), 4(14), 4(17) or 4(21).

EXAMPLE 5(1)N²-(2-chloro-4-methoxyphenyl)-N²-methyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.20 (toluene:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.70, 1.40, 1.95, 2.75, 2.90, 3.14, 3.37,3.80, 6.80, 6.98, 7.18.

EXAMPLE 5(2)N²-(5,7-dimethyl-2,1,3-benzothiazol-4-yl)-N²-methyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.49 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, DMSO-d₆): δ 0.56, 1.21, 1.89, 2.25, 2.58, 2.64, 2.87,3.07, 3.40, 7.41.

EXAMPLE 5(3)N²-(5,7-dimethyl-2,1,3-benzothiazol-4-yl)-N²-methyl-N⁴,N⁴-dipropyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

TLC: Rf 0.48 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 0.58, 1.24, 2.27, 2.65, 2.96, 3.42, 4.60,5.03, 7.42.

EXAMPLE 5(4)N⁵-(2-chloro-4-methoxyphenyl)-N⁵,6-dimethyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.40 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.78, 1.40, 1.55, 3.31, 3.81, 6.32, 6.71,6.82, 7.03, 7.90.

EXAMPLE 5(5)N⁵-(2-chloro-4-methoxyphenyl)-N⁵,6-dimethyl-N⁷,N⁷-dipropyl[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine

TLC- Rf 0.30 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.77, 1.41, 1.51, 3.30, 3.37, 3.81, 6.73,6.86, 7.02, 8.16.

EXAMPLE 5(6)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.30 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.77, 1.53, 3.41, 3.85, 4.78, 6.15, 6.89,7.06, 7.23, 7.81.

EXAMPLE 5(7)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-methyl-N⁷,N⁷-dipropyl[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.28 (toluene:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.78, 1.55, 3.45, 3.85, 4.75, 6.90, 7.07,7.23, 8.04.

EXAMPLE 5(8)N⁷-(2-chloro-4-methoxyphenyl)-N⁷-methyl-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.36 (ethyl acetate:methanol 10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.80, 1.48, 2.97, 3.45, 3.86, 5.09, 6.89,7.06, 7.12, 7.21, 7.37.

EXAMPLE 5(9)N²-(2,4-dichlorophenyl)-N²-methyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.26 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.44, 7.26-7.19, 3.38, 3.14, 2.90, 2.75,1.96, 1.41, 0.72.

EXAMPLE 6N²-(2-chloro-4-methoxyphenyl)-N⁴-(1-ethylpropyl)-N²-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The mixture was 2-chloro-4-methoxy-N-methylaniline (150 mg) and2-chloro-4-(1-ethylpropylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(322 mg) was heated for 9 hours at 120° C., and then for 6 hours at 160°C. The reaction mixture was cooled to room temperature, a crude productwas purified by column chromatography on silica gel (toluene:ethylacetate=1:1→1:3) to give the title compound (147 mg) as dark brown oilhaving the following physical data.

TLC: Rf 0.21 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.76, 1.37, 2.04, 2.52, 2.77, 3.37, 3.56,3.81, 6.81, 6.98, 7.18.

EXAMPLE 6(1)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)-N⁵-methyl[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 6 using acorresponding compound.

TLC: Rf 0.23 (toluene:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.85, 1.51, 3.00, 3.46, 3.87, 4.78, 5.50,6.91, 7.09, 7.24, 8.07.

EXAMPLE 72-(methylthio)-N,N-dipropylpyrazolo[1,5-a][1,3,5]triazine-4-amine

To a solution of 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine(1.0 g) in tefrahydrofuran (5.0 mL), triethylamine (1.0 mL) anddi-n-propylamine (1.0 mL) were added at 0° C. The mixture was stirredovernight at room temperature. The reaction solution was filteredthrough celite, concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=10:1) to give the title compound (1.1 g) as a white powderhaving the following physical data.

TLC: Rf 0.85 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.95, 1.75, 2.52, 3.94, 6.13, 7.83.

EXAMPLE 82-(methylsulfonyl)-N,N-dipropylpyrazolo[1,5-a][1,3,5]triazine-4-amine

To a solution of the compound prepared in Example 7 (660 mg) inmethylene chloride (11 mL), m-chloroperbenzoic acid (1.1 g) was added,and the mixture was stirred for 4 hours at room temperature. To thereaction mixture, an aqueous solution of sodium sulfite was added. Themixture was extracted with methylene chloride. The organic layer waswashed with 2N aqueous solution of sodium hydroxide and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give the titlecompound (590 mg) as a white powder having the following physical data.

TLC: Rf 0.62 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.98, 1.80, 3.27, 3.74, 4.30, 6.54, 8.02.

EXAMPLE 9N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

The title compound (70 mg) as a white powder having the followingphysical data was obtained by the same procedure as a series ofreactions of Example 6 using a compound prepared in Example 8 (250 mg)and 2-chloro-4-methoxyaniline (280 mg).

TLC: Rf 0.68 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.94, 1.74, 3.78, 3.89, 5.96, 6.83, 6.90,6.94, 7.77, 8.22.

EXAMPLE 10N²-(2-chloro-4-methoxyphenyl)-N²-methyl-N⁴,N⁴-dipropylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

The title compound (41 mg) as a white powder having the followingphysical data was obtained by the same procedure as a series ofreactions of Example 5 using a compound prepared in Example 9 (42 mg).

TLC: Rf 0.67 (hexane:ethyl acetate=3:1);

¹H-NMR(300 MHz, CDCl₃): δ 0.75, 1.53, 3.57, 5.96, 6.81, 6.98, 7.17,7.71.

EXAMPLE 11 2,6-dichloro-5-nitro-N,N-dipropylpyrimidine-4-amine

To a solution of 2,4,6-trichloro-5-nitropyrimidine (1.7 g) intetrahydrofuran (20 mL), di-n-propylamine (1.03 mL) and triethylamine(1.04 mL) were dropped at 0° C. The mixture was stirred for 2 hours. Thereaction mixture was diluted with ethyl acetate. The diluted solutionwas washed with water and a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the title compound having the followingphysical data.

TLC: Rf 0.50 (hexane:ethyl acetate=20:1);

¹H-NMR (300 MHz, CDCl₃): δ 3.36, 1.61, 0.91.

EXAMPLE 12 2-chloro-5-nitro-N,N-dipropylpyrimidine-4,6-diamine

To a solution of the compound prepared in Example 11 (2.26 g) in ethanol(15 mL), a solution of ammonia in ethanol (7 mL) was added, and then themixture was stirred for 2 hours at room temperature. The reactionmixture was diluted with ethyl acetate. The diluted solution was washedwith water and a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=8:1) to give the title compound (534 mg) as ayellow crystal having the following physical data.

TLC: Rf 0.24 (hexane:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 3.37, 1.62, 0.90.

EXAMPLE 13N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-N²-methyl-5-nitropyrimidine-2,4,6-triamine

The title compound (691 mg) as pale yellow oil having the followingphysical data was obtained by the same procedure as a series ofreactions of Example 6 using a compound prepared in Example 12 (534 mg)and N-(2-chloro-4-methoxyphenyl)-N-methylamine (1.3 g).

TLC: Rf 0.33 (hexane:ethyl acetate=4:1).

EXAMPLE 14N-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-N²-methylpyrimidine-2,4,5,6-tetraamine

To a solution of the compound prepared in Example 13 (440 mg) in ethanol(12 mL), water (10 mL) was added, and then sodium dithionite (1.5 g) wasadded at 50° C. The mixture was stirred for 30 minutes. After thereaction mixture was cooled, it was diluted with ethyl acetate. Thediluted solution was washed with water and a saturated aqueous solutionof sodium chloride, dried over magnesium sulfate and concentrated underreduced pressure to give the title compound (443 mg) as a brown solidhaving the following physical data.

TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.16, 6.99, 6.84, 6.01, 3.81, 3.40, 3.23,1.47, 0.75.

EXAMPLE 15N⁵-(2-chloro-4-methoxyphenyl)-N⁵-methyl-N⁷,N⁷-dipropyl[1,2,5]thiadiazol[3,4-d]pyrimidine-5,7-diamine

Thionyl chloride (5.0 mL) was added to the compound prepared in Example14 (437 mg), and the mixture was refluxed for 2.5 hours. After thereaction mixture was cooled, it was poured into an ice-water. Thesolution was basified by adding a saturated aqueous solution of sodiumbicarbonate and extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium bicarbonate and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (hexane:ethylacetate=5:1 ) to give the title compound (344 mg) as a pale yellow solidhaving the following physical data.

TLC: Rf 0.45 (hexane:ethyl acetate=4:1);

¹H-NMR(300 MHz, DMSO-d₆): δ 0.77, 1.55, 3.74, 6.96, 7.10, 7.30.

EXAMPLE 16N²-mesityl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3 (using acompound prepared in a series of reactions of Example 1→Example 2 usinga corresponding compound)→Example 4 (using a corresponding compound).

TLC: Rf 0.34 (ethyl acetate:methanol=100:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.68, 1.39, 1.98, 2.19, 2.26, 2.71, 2.91,3.16, 5.85, 6.87.

EXAMPLE 172-[(2-chloro-4-methoxyphenyl)amino]-4-(dipropylamino)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3 (using acompound prepared in a series of reactions of Example 1- Example 2 usinga corresponding compound)→Example 4.

TLC: Rf 0.68 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.89, 1.64, 1.78, 2.00, 2.66, 3.51, 3.77,6.25, 6.73, 6.92, 6.99.

EXAMPLE 18N²-(2-chloro-4-methoxyphenyl)-3-methyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2,4-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3 (using acompound prepared in a series of reactions of Example 1→Example 2 usinga corresponding compound)→Example 4.

TLC: Rf 0.61 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.28, 6.94, 6.82, 6.48, 3.77, 2.93-3.04,2.80-2.92, 2.20, 1.97-2.12, 1.34-1.52, 0.84.

EXAMPLE 19 6-methylpyrazolo[1,5-a]pyrimidin-5,7-diol

Under argon gas atmosphere, sodium (6.92 g) was added to ethanol (250mL) by little and little, and the ethanol solution was stirred untilsodium was solved completely at room temperature. A solution of3-aminopyrazole (25.0 g) in ethanol (20 mL) and diethyl methylmalonate(52 mL) were dropped, successively, to the above solution. The mixturewas refluxed at 90° C. After the reaction mixture was cooled to roomtemperature, the mixture was filtrated under vacuum. The solid wassolved to cooled 5N hydrochloric acid (70 mL). The precipitate wascollected by filtration and dried under vacuum to give the titlecompound (36.7 g).

EXAMPLE 20 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine

Under argon gas atmosphere, phosphoryl chloride (102 g) andN,N-diethylaniline (8.4 g), successively, was dropped into the compoundprepared in Example 19. The mixture was refluxed for 4 hours at 150° C.Besides, N,N-diethylaniline (8.4 g) was dropped into the above mixture,and the mixture was refluxed at same temperature. After the reactionmixture was cooled to room temperature, it was concentrated underreduced pressure. The residue was solved into an ice-water. An aqueoussolution of sodium bicarbonate was added to the solution. The mixturewas neutralized and then filtrated through celite. The filtrate wasextracted twice with ethyl acetate. The organic layer was water andnormal saline solution, successively, dried over magnesium sulfate,filtrated and concentrated under reduced pressure. The obtained residuewas purified by column chromatography on silica gel (hexane:ethylacetate=12:1, 10:1, 8:1, 6:1 ) to give the title compound (22.2 g)having the following physical data.

TLC: Rf 0.46 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 2.56, 6.70, 8.16.

EXAMPLE 21N⁵-(4-methoxy-2-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3 using5,7-dichloro-6-methyl-pyrazolo[1,5-a]pyrimidine→corresponding Example 4.

TLC: Rf 0.29 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.49, 2.28, 2.29, 3.34, 3.81, 6.04,6.14, 6.81, 7.70, 7.81.

EXAMPLE 21(1)-21(89)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 19→Example 20→Example 3→Example 4, using acorresponding compound.

EXAMPLE 21(1)N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.18 (hexane:ethyl acetate=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.42, 1.50, 2.34, 3.34, 4.03, 6.23,6.90, 6.98, 7.86, 8.61.

EXAMPLE 21(2)N⁵-mesityl-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.52 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.51, 2.20, 2.31, 2.32, 3.34, 5.76,6.07, 6.95, 7.77.

EXAMPLE 21(3)N⁵-(2,4-dimethylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.50 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.40-1.58, 2.28, 2.30, 2.32, 3.35,6.10-6.20, 7.01-7.12, 7.77-7.88.

EXAMPLE 21(4)N⁵-(2-fluoro-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.64 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.32-1.64, 2.32, 2.33-2.36, 3.36, 6.25,6.63, 6.83-7.09, 7.87, 8.52.

EXAMPLE 21(5)N⁵-(2-fluoro-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.68 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.23-1.77, 2.33, 2.36, 3.36, 6.26,7.08, 7.14, 7.22, 7.88, 8.67.

EXAMPLE 21(6)3-chloro-4-{[7-(dipropylamino)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl]amino}benzonitrile

TLC: Rf 0.53 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.30-1.70, 2.38, 3.09-3.64, 6.36, 7.47,7.62, 7.69, 7.94, 9.15.

EXAMPLE 21(7)N⁵-(2,4-dimethoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.43 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.35-1.63, 2.31, 3.18-3.50, 3.83, 3.91,6.21, 6.48-6.65, 7.06, 7.84, 8.64.

EXAMPLE 21(8)N⁵-(4-fluoro-2-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.39 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.89, 7.83, 6.96, 6.16, 6.09, 3.35, 2.30,1.48, 0.87.

EXAMPLE 21(9)4-{[7-(dipropylamino)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl]amino}-3-methylbenzonitrile

TLC: Rf 0.68 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.70, 7.92, 7.58, 7.49, 6.53, 6.32, 3.39,2.38, 2.35, 1.49, 0.87.

EXAMPLE 21(10)N⁵-(4-chloro-2-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.46 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.09, 7.85, 7.12-7.32, 6.20, 6.18, 3.26-3.45,2.31, 1.40-1.60, 0.87.

EXAMPLE 21(11)N⁵-(4-chloro-2-fluorophenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.62 (toluene:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.73, 7.89, 7.09-7.23, 6.68, 6.27, 3.25-3.45,2.32, 1.38-1.57, 0.86.

EXAMPLE 21(12)N⁵-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.66 (toluene:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.98, 7.92, 7.47, 7.38, 6.90, 6.32,3.21-3.55, 2.35, 1.38-1.60, 0.86.

EXAMPLE 21(13)N⁵-(2,4-difluorophenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.54 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.58-8.71, 7.88, 6.83-7.02, 6.56, 6.25, 3.36,2.32, 1.39-1.60, 0.86.

EXAMPLE 21(14)N⁵-[2-chloro-4-(trifluoromethyl)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.64 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 9.08, 7.93, 7.67, 7.59, 7.37, 6.33,3.26-3.50, 2.39, 1.39-1.59, 0.87.

EXAMPLE 21(15)4-{[7-(dipropylamino)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl]amino}-3-ethylbenzonitrile

TLC: Rf 0.29 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.66, 7.91, 7.57, 7.50, 6.62, 6.30,3.27-3.49, 2.71, 2.34, 1.42-1.61, 1.36, 0.87.

EXAMPLE 21(16)N⁵-(2-chloro-4-fluorophenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.59 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.81, 7.89, 7.17, 7.04-7.13, 7.02, 6.26,3.37, 2.36, 1.41-1.58, 0.87.

EXAMPLE 21(17)N⁵-(2,4-dichlorophenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.65 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.86, 7.90, 7.41, 7.31, 7.14, 6.29, 3.37,2.36, 1.38-1.61, 0.86.

EXAMPLE 21(18)N⁵-(4-chloro-2,5-dimethoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.48 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.81, 7.88, 7.31, 6.91, 6.23, 3.97, 3.91,3.35, 2.32, 1.38-1.55, 0.86.

EXAMPLE 21(19)N⁵-[4-fluoro-2-(trifluoromethyl)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.51 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.52, 7.88, 7.19-7.44, 6.79, 6.22, 3.22-3.48,2.29, 1.39-1.62, 0.87.

EXAMPLE 21(20)N⁵-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.56 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.64, 7.89, 7.59, 7.54, 6.91, 6.25,3.29-3.43, 2.29, 1.33-1.60, 0.87.

EXAMPLE 21(21)N⁵-(2-chloro-4,6-dimethylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.40 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.80, 7.13, 7.02, 6.10, 6.07, 3.30-3.41,2.35, 2.32, 2.24, 1.38-1.63, 0.88.

EXAMPLE 21(22)6-methyl-N⁵-[2-methyl-4-(trifluoromethoxy)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.45 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.19, 7.86, 7.05-7.18, 6.15-6.27, 3.25-3.46,2.34, 2.32, 1.40-1.59, 0.87.

EXAMPLE 21(23)6-methyl-N⁷,N⁷-dipropyl-N⁵-(2,4,5-trimethylphenyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.45 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.82, 7.61, 7.00, 6.17, 6.09, 3.35, 2.28,2.26, 2.24, 2.23, 1.41-1.57, 0.87.

EXAMPLE 21(24)N⁵-(5-chloro-2,4-dimethoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.37(hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.85, 7.86, 7.05, 6.58, 6.28, 3.96, 3.91,3.34, 2.30, 1.37-1.55, 0.86.

EXAMPLE 21(25)N⁵-(4,5-dimethoxy-2-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.26 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.83, 7.53, 6.74, 6.15, 6.08, 3.89, 3.88,3.35, 2.30, 2.25, 1.42-1.56, 0.87.

EXAMPLE 21(26)N⁵-(6-methoxy-2,3-dihydro-1H-inden-5-yl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.51 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.58, 7.85, 6.81, 6.25, 3.91, 3.21-3.47,2.95, 2.89, 2.32, 2.01-2.15, 1.39-1.55, 0.86.

EXAMPLE 21(27)N⁵-(2,6-dimethyl-3-pyridinyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.26 (hexane:ethyl acetate=1:3);

¹H-NMR (300 MHz, CDCl₃): δ 8.34, 7.86, 7.07, 6.19, 6.16, 3.25-3.47,2.55, 2.53, 2.33, 1.40-1.58, 0.87.

EXAMPLE 21(28)N⁵-(2,6-dimethylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.40 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.78, 7.13, 6.06, 5.81, 3.21-3.46, 2.33,2.24, 1.41-1.62, 0.89.

EXAMPLE 21(29)N⁵-(4-chloro-2-methoxy-5-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.42 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.68, 7.87, 7.19, 6.88, 6.28, 3.92, 3.35,2.39, 2.31, 1.34-1.59, 0.86.

EXAMPLE 21(30) Methyl3-chloro-4-{[7-(dipropylamino)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl]amino}benzoate

TLC: Rf 0.37 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 9.04, 8.10, 8.02, 7.93, 7.47, 6.35, 3.92,3.29-3.46, 2.39, 1.40-1.61, 0.86.

EXAMPLE 21(31)6-methyl-N⁵-(4-methyl-2-vinylphenyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.41 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.88, 7.83, 7.28, 7.14, 6.87, 6:30, 6.17,5.70, 5.38, 3.35, 2.36, 2.28, 1.39-1.61, 0.87.

EXAMPLE 21(32)N⁵-[4-chloro-2-(trifluoromethoxy)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.73 (toluene:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.87, 7.89, 7.26-7.36, 6.89, 6.28, 3.27-3.45,2.31, 1.40-1.56, 0.86.

EXAMPLE 21(33)N⁵-(2-ethyl-4-methoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.42 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.80, 7.67, 6.71-6.89, 6.12, 6.06, 3.82,3.19-3.47, 2.63, 2.28, 1.39-1.58, 1.25, 0.87.

EXAMPLE 21(34)6-methyl-N⁷,N⁷-dipropyl-N⁵-(2,4,6-trimethyl-3-pyridinyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.51 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.78, 6.94, 6.05, 5.75, 3.18-3.50, 2.51,2.44, 2.33, 2.20, 1.37-1.63, 0.88.

EXAMPLE 21(35)6-methoxy-N⁷-(2-methoxyethyl)-N⁷-propyl-N⁵-(2,4,5-trimethylphenyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.36 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.89, 7.81, 6.99, 6.94, 6.16, 3.99, 3.86,3.56-3.63, 3.52, 3.25, 2.25-2.30, 2.22, 1.54-1.67, 0.87.

EXAMPLE 21(36)3-chloro-4-{[7-(dipropylamino)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl]amino}-N-methylbenzamide

TLC: Rf 0.57 (methylene chloride:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.99, 7.89-7.93, 7.65, 7.38, 6.32, 6.07,3.30-3.45, 2.99-3.05, 2.38, 1.41-1.56, 0.86.

EXAMPLE 21(37)N⁵-(3,5-dichloro-2-pyridinyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.48 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.41-1.63, 2.19, 3.29-3.59, 6.36, 7.08,7.68, 7.93, 8.16.

EXAMPLE 21(38) N⁵-[2-chloro-4-(trifluoromethoxy)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.61 (toluene:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.38-1.59, 2.37, 3.22-3.50, 6.28, 7.14,7.17-7.27, 7.31, 7.89, 8.93.

EXAMPLE 21(39)N⁵-[4-isopropyl-2-(methylsulfanyl)phenyl]-6-methyl-N⁷,N⁷-dipropylprazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.58 (toluene:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.26, 1.40-1.57, 2.37, 2.41, 2.79-2.96,3.35, 6.23, 7.23, 7.37, 7.85, 7.89, 8.63.

EXAMPLE 21(40)N⁵-(2-ethyl-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.40 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.26, 1.39-1.58, 2.29, 2.34, 2.64,3.35, 6.16, 6.19, 7.01-7.12, 7.75-7.86.

EXAMPLE 21(41)N⁵-(4-chloro-2-ethylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.38 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.29, 1.41-1.57, 2.30, 2.65, 3.36,6.19, 6.24, 7.18-7.28, 7.85, 8.06.

EXAMPLE 21(42)N⁵-mesityl-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.49 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.90, 1.53-1.71, 2.23, 2.30, 3.51-3.66, 3.84,6.04, 6.42, 6.95, 7.77.

EXAMPLE 21(43)N⁵-mesityl-N⁷,N⁷-bis(2-methoxyethyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.36 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.76, 6.95, 6.07, 5.79, 3.56-3.68, 3.45,3.28, 2.35, 2.31, 2.19.

EXAMPLE 21(44)N⁵-(4,6-dimethyl-3-pyridinyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.26 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.41-1.58, 2.26, 2.32, 2.53, 3.28-3.43,6.05, 6.13, 7.05, 7.83, 8.80.

EXAMPLE 21(45)N⁵-(4-chloro-2-methoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.56 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.85, 1.37-1.56, 2.32, 3.34, 3.94, 6.26,6.88, 7.01, 7.24, 7.86, 8.78.

EXAMPLE 21(46)6-methoxy-N⁷,N⁷-dipropyl-N⁵-(2,4,5-trimethylphenyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.40 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.89, 1.51-1.69, 2.22, 2.27, 2.28, 3.52-3.64,3.82, 6.16, 6.90, 6.98, 7.82, 7.87.

EXAMPLE 21(47)6-methoxy-N⁵-(4-methyl-2-vinylphenyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.49 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.52-1.68, 2.35, 3.52-3.63, 3.81, 5.39,5.70, 6.16, 6.89, 7.12, 7.15, 7.23-7.30, 7.83, 8.10.

EXAMPLE 21(48)N⁵-[2-chloro-4-(methylsulfonyl)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.61 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.41-1.57, 2.40, 3.08, 3.31-3.51, 6.36,7.49, 7.89, 7.95, 7.99, 9.18.

EXAMPLE 21(49)N⁵-(2-ethyl-4,5-dimethoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.49 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.25, 1.42-1.57, 2.29, 2.62, 3.35,3.88, 3.90, 6.13, 6.14, 6.76, 7.49, 7.82.

EXAMPLE 21(50)N⁵-(2-ethyl-4-methylphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.34 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.07, 7.82, 7.00-7.11, 6.14, 3.82, 3.53-3.63,2.66, 2.33, 1.53-1.68, 1.27, 0.88.

EXAMPLE 21(51)N⁵-(4-chloro-2-ethylphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.40 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.34, 7.85, 7.16-7.29, 7.12, 6.18, 3.82,3.53-3.65, 2.67, 1.52-1.69, 1.30, 0.88.

EXAMPLE 21(52)N⁵-(2,4-dimethyl-6-vinylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.27 (hexane:acetone=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.89, 1.43-1.60, 2.18, 2.31, 2.35, 3.25-3.44,5.22, 5.67, 5.81, 6.07, 6.81, 7.05, 7.27, 7.78.

EXAMPLE 21(53)N⁵-(2-ethyl-4,6-dimethylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.30 (hexane:acetone=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.89, 1.17, 1.43-1.59, 2.19, 2.32, 2.33,2.57, 3.34, 5.77, 6.06, 6.97, 7.77.

EXAMPLE 21(54)N⁵-(2-isopropenyl-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.58 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.37-1.56, 2.09, 2.22, 2.33, 3.33,5.10, 5.37-5.46, 6.22, 6.97, 7.02, 7.13, 7.84, 8.47.

EXAMPLE 21(55)N⁵-(2-isopropyl-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.50 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.27, 1.42-1.58, 2.29, 2.36, 3.01-3.18,3.35, 6.13, 6.15, 7.05, 7.13, 7.61, 7.81.

EXAMPLE 21(56)N⁵-(2-ethyl-4-methoxyphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.31 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.89-7.96, 7.81, 6.87, 6.79-6.84, 6.11, 3.83,3.82, 3.54-3.62, 2.66, 1.53-1.69, 1.27, 0.89.

EXAMPLE 21(57)6-methyl-N⁵-[4-(methylsulfanyl)-2-(trifluoromethyl)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.51 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.41-1.59, 2.29, 2.52, 3.29-3.44, 6.23,6.87, 7.46-7.55, 7.88, 8.53.

EXAMPLE 21(58)N⁵-[4-isopropyl-2-(methylsulfinyl)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.45 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.25, 1.26, 1.42-1.58, 2.32, 2.83-2.96,2.93, 3.23-3.49, 6.23, 7.16, 7.40, 7.88, 8.64, 9.72.

EXAMPLE 21(59)N⁵-[4-isopropyl-2-(methylsulfonyl)phenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.62 (hexane:ethyl acetate=2:1);

¹H-NMR(300 MHz, CDCl₃): δ 0.87, 1.28, 1.42-1.59, 2.32, 2.90-3.03, 3.07,3.31-3.44, 6.25, 7.53, 7.77, 7.90, 8.61, 8.78.

EXAMPLE 21(60)N⁵-(2-chloro-4,5-dimethylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.72 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.39-1.57, 2.22, 2.30, 2.34, 3.36,6.27, 6.98, 7.15, 7.87, 8.50.

EXAMPLE 21(61)N⁵-(5-chloro-2,3-dimethylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.62 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.42-1.56, 2.17, 2.30, 2.31, 3.30-3.42,6.19, 6.21, 6.98, 7.84, 7.85.

EXAMPLE 21(62)N⁵-[2-(dimethylamino)-4-methylphenyl]-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.68 (toluene:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.38-1.56, 2.32, 2.70, 3.34, 6.23,6.96-7.02, 7.85, 8.16, 8.65.

EXAMPLE 21(63)6-methoxy-N⁷-(2-methoxyethyl)-N⁵-(4-methyl-2-vinylphenyl)-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.38 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.12, 7.82, 7.24-7.29, 7.12-7.19, 6.89, 6.16,5.70, 5.40, 3.99, 3.85, 3.55-3.64, 3.48-3.55, 3.25, 2.35, 1.54-1.65,0.87.

EXAMPLE 21(64)N⁵-(2-ethyl-4-methylphenyl)-6-methoxy-N⁷-(2-methoxyethyl)-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.35 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.09, 7.81, 7.02-7.13, 6.15, 3.98, 3.86,3.55-3.64, 3.52, 3.25, 2.67, 2.33, 1.52-1.66, 1.28, 0.87.

EXAMPLE 21(65)N⁵-(4-chloro-2-ethylphenyl)-6-methoxy-N⁷-(2-methoxyethyl)-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.39 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.36, 7.84, 7.21-7.27, 7.20, 7.17, 6.19,4.01, 3.87, 3.56-3.65, 3.52, 3.24, 2.68, 1.52-1.67, 1.31, 0.87.

EXAMPLE 21(66)6-methyl-N⁷,N⁷-dipropyl-N⁵-(2,3,5-trimethyl-4-pyridinyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.34 (methylene chloride:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.89, 1.43-1.64, 2.15, 2.18, 2.34, 2.54,3.28-3.45, 5.85, 6.12, 7.82, 8.24.

EXAMPLE 21(67)N⁵-(2-cyclopropyl-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.61 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.66-0.78, 0.87, 0.94-1.07, 1.39-1.57,1.74-1.92, 2.31, 2.35, 3.35, 6.23, 7.00, 7.10, 7.17, 7.85, 8.42.

EXAMPLE 21(68)N⁵-[4-isopropyl-2-(methylsulfanyl)phenyl]-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.60 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.69, 8.45, 7.86, 7.38, 7.23, 6.21, 3.85,3.54-3.66, 2.81-2.96, 2.42, 1.52-1.68, 1.26, 0.88.

EXAMPLE 21(69)N⁵-(4-cyclopropyl-2-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.61 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.64-0.72, 0.87, 0.90-0.97, 1.40-1.57,1.80-1.93, 2.28, 2.29, 3.35, 6.14, 6.16, 6.92-6.99, 7.80-7.89.

EXAMPLE 21(70)N⁵-(2-ethyl-4-methoxyphenyl)-N⁷-(2-methoxyethyl)-6-methyl-N⁷-propylpyrazolo-1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.25 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.80, 7.69, 6.77-6.85, 6.13, 6.10, 3.83,3.56-3.68, 3.42, 3.31-3.39, 3.28, 2.64, 2.30, 1.43-1.58, 1.25, 0.88.

EXAMPLE 21(71)N⁵-(2-ethyl-4-methylphenyl)-N⁷-(2-methoxyethyl)-6-methyl-15-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.33 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.77-7.85, 7.03-7.11, 6.22, 6.16, 3.56-3.67,3.42, 3.33-3.39, 3.27, 2.64, 2.34, 2.31, 1.43-1.58, 1.26, 0.87.

EXAMPLE 21(72)N⁵-(4-chloro-2-ethylphenyl)-N⁷-(2-methoxyethyl)-6-methyl-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.38 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.02-8.11, 7.84, 7.18-7.28, 6.27, 6.20,3.58-3.69, 3.42, 3.32-3.38, 3.26, 2.65, 2.32, 1.42-1.58, 1.29, 0.87.

EXAMPLE 21(73)N⁵-(2-methyl-4-ethylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.52 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.24, 1.42-1.57, 2.30, 2.62, 3.35,6.16, 6.17, 7.03-7.14, 7.83, 7.89.

EXAMPLE 21(74)N⁵-(2-methyl-4-vinylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.52 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.41-1.56, 2.31, 2.34, 3.36, 5.18,5.69, 6.21, 6.28, 6.69, 7.28, 7.33, 7.85, 8.14.

EXAMPLE 21(75)N⁵-(3,5-dimethyl-2-pyridinyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.61 (hexane:ethyl acetate=1:5);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.42-1.57, 2.24, 2.25, 2.30, 3.27-3.46,6.16, 6.57, 7.39, 7.84, 8.04.

EXAMPLE 21(76)6-methyl-N⁵-[4-methyl-2-(methylsulfanyl)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.63 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.40-1.57, 2.33, 2.37, 2.40, 3.35,6.24, 7.17, 7.33, 7.86, 7.88, 8.62.

EXAMPLE 21(77)6-methyl-N⁵-[2-methyl-4-(methylsulfanyl)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.57 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.41-1.56, 2.30, 2.49, 3.28-3.43,6.16-6.22, 7.14-7.24, 7.84, 8.03.

EXAMPLE 21(78)6-methyl-N⁵-[2-methyl-4-(methylsulfinyl)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.53 (methanol:ethyl acetate=1:9);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.40-1.57, 2.34, 2.42, 2.74, 3.27-3.47,6.26, 6.43, 7.49, 7.58, 7.89, 8.54.

EXAMPLE 21(79)6-methyl-N⁵-[2-methyl-4-(methylsulfonyl)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.33 (hexane:ethyl acetate 1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.41-1.58, 2.35, 2.42, 3.05, 3.27-3.53,6.31, 6.54, 7.77, 7.83, 7.91, 8.70.

EXAMPLE 21(80)N⁵-(4-isopropyl-2-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.63 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.25, 1.41-1.56, 2.29, 2.31, 2.79-2.96,3.35, 6.13-6.20, 7.08, 7.12, 7.83, 7.92.

EXAMPLE 21(81)N⁷-(methoxyethyl)-6-methyl-N⁵-(4-methyl-2-vinylphenyl)-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.38 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.41-1.58, 2.29, 2.36, 3.27, 3.32-3.39,3.42, 3.57-3.68, 5.38, 5.70, 6.18, 6.33, 6.86, 7.15, 7.28, 7.82, 7.88.

EXAMPLE 21(82)N⁵-[4-isopropyl-2-(methylsulfanyl)phenyl]-N⁷-(2-methoxyethyl)-6-methyl-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.56 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.26, 1.43-1.58, 2.39, 2.41, 2.83-2.95,3.26, 3.33-3.39, 3.42, 3.57-3.69, 6.25, 7.20-7.28, 7.39, 7.86, 7.93,8.65.

EXAMPLE 21(83)N⁵-(2-ethyl-4,5-dimethoxyphenyl)-N⁷-(2-methoxyethyl)-6-methyl-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.43 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): 6 0.88, 1.25, 1.44-1.60, 2.31, 2.61, 3.28,3.32-3.40, 3.43, 3.57-3.68, 3.88, 3.90, 6.14, 6.15, 6.76, 7.50, 7.82.

EXAMPLE 21(84)N⁵-(4-ethyl-6-methyl-3-pyridinyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.31 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.26, 1.41-1.59, 2.31, 2.55, 2.62,3.25-3.51, 6.05, 6.13, 7.08, 7.83, 8.81.

EXAMPLE 21(85)N⁵-(4-isopropyl-2-vinylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.50 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.27, 1.40-1.59, 2.26, 2.82-3.01, 3.35,5.40, 5.72, 6.19, 6.41, 6.89, 7.21, 7.30, 7.84, 7.94.

EXAMPLE 21(86)N⁵-(4-ethyl-2-isopropylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.49 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.26, 1.28, 1.42-1.57, 2.27, 2.67,2.81-2.99, 3.35, 6.17, 6.30, 7.07-7.16, 7.83, 7.88.

EXAMPLE 21(87)N⁵-(4-chloro-2-(methylsulfanyl)phenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.73 (toluene: ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.75, 7.88, 7.86, 7.47, 7.31, 6.27, 3.36,2.44, 2.37, 1.49, 0.87.

EXAMPLE 21(88)N⁵-(2-methyl-4-(2-dimethylaminoethoxy)phenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.28 (ethyl acetate:methanol:triethylamine=9:1:0.3);

¹H-NMR (300 MHz, CDCl₃): δ 7.81, 7.69, 6.86-6.78, 6.13, 6.05, 4.08,3.34, 2.75, 2.36, 2.29, 2.27, 1.49, 0.87.

EXAMPLE 21(89)N⁵-(2-methyl-4-(3-dimethylaminopropoxy)phenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.25 (ethyl acetate:methanol:triethylamine=9:1:0.3);

¹H-NMR (300 MHz, CDCl₃): δ 7.81, 7.66, 6.84-6.75, 6.13, 6.04, 4.02,3.34, 2.48, 2.29, 2.28, 2.27, 1.97, 1.49, 0.87.

EXAMPLE 22(1)-EXAMPLE 22(7)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 3→Example 4, using a corresponding compoundprepared by the same procedure as a series of reactions of Example19→Example 20.

EXAMPLE 22(1)N⁵-(2-chloro-4-methoxyphenyl)-6-ethyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3→Example 4,using 5,7-dichloro-6-ethylpyrazolo[1,5-a]pyrimidine.

TLC: Rf 0.34 (hexane:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.64, 7.86, 7.04, 6.98, 6.92, 6.22, 3.81,3.24-3.39, 2.92, 1.41-1.58, 1.35, 0.88.

EXAMPLE 22(2)N⁵-(2-chloro-4-methoxyphenyl)-N⁷,N⁷,6-tripropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0:32 (hexane:ethyl acetate=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.13, 1.50, 1.72, 2.82, 3.29, 3.81,6.22, 6.91, 6.98, 7.05, 7.86, 8.68.

EXAMPLE 22(3)N⁵-(2-chloro-4-methoxyphenyl)-6-isopropyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.64 (hexane:ethyl acetate=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.50, 3.20, 3.38, 3.81, 4.24, 6.20,6.91, 6.98, 7.09, 7.85, 8.63.

EXAMPLE 22(4)N⁵-(2-chloro-4-methoxyphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.5 (hexane:ethyl acetate=10:1);

¹H-NMR (300 MHz, CDCl₃): δ0.88, 1.60, 3.60, 3.81, 3.85, 6.20, 6.91,6.98, 7.67, 7.86, 8.70.

EXAMPLE 22(5)6-butyl-N⁵-(2-chloro-4-methoxyphenyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.3 (hexane:ethyl acetate=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.03, 1.58, 2.84, 3.30, 3.81, 6.22,6.92, 6.98, 7.05, 7.86, 8.67.

EXAMPLE 22(6)N⁵-(2-chloro-4-methoxyphenyl)-6-phenyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.24 (hexane:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.75, 1.41, 3.08, 3.76, 6.24, 6.74, 6.86,7.45, 7.57, 7.91, 8.61.

EXAMPLE 22(7)N⁵-(2-chloro-4-methoxyphenyl)-6-cyclopentyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.28 (hexane:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.46, 1.81, 1.98, 3.31, 3.81, 4.22,6.18, 6.69, 6.90, 6.97, 7.85, 8.37.

EXAMPLE 23(1)-EXAMPLE 23(38)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 3- Example 4, using a corresponding amine.

EXAMPLE 23(1)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(2-methoxyethyl)-6-methyl-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.13 (hexane:ethyl acetate=6:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.40-1.58, 2.36, 3.26, 3.29-3.50,3.52-3.72, 3.81, 6.23, 6.87-6.97, 6.98, 7.86, 8.63.

EXAMPLE 23(2)N⁵-(2-chloro-4-methoxyphenyl)-N⁷,N⁷-bis(2-methoxyethyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 2.38, 3.26, 3.38-3.48, 3.53-3.72, 3.81, 6.24,6.87-6.96, 6.99, 7.85, 8.63.

EXAMPLE 23(3)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(cyclopropylmethyl)-6-methyl-N⁷-(4-methylbenzyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.36 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ-0.13-0.02, 0.25-0.41, 0.78-0.95, 2.31, 2.34,3.08-3.35, 3.81, 4.57, 6.25, 6.86-6.95, 6.98, 7.07, 7.19, 7.90, 8.64.

EXAMPLE 23(4)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(cyclopropylmethyl)-N⁷-(2-methoxyethyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.38 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.09-0.10, 0.29-0.46, 0.81-0.98, 2.41,3.21-3.36, 3.37-3.49, 3.55-3.76, 3.81, 6.24, 6.92, 6.96, 6.99, 7.85,8.66.

EXAMPLE 23(5)N-(2-chloro-4-methoxyphenyl)-N⁷-ethyl-7-(2-methoxyethyl)-6-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.32 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.64, 7.85, 6.99, 6.88-6.96, 6.23, 3.81,3.56-3.70, 3.35-3.55, 3.27, 2.37, 1.06.

EXAMPLE 23(6)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(cyclopropylmethyl)-6-methyl-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.30 (hexane:ethyl acetate=8:1);

¹H-NMR(300 MHz, CDCl₃): δ -0.11-0.09, 0.28-0.44, 0.78-0.97, 1.39-1.56,2.41, 3.15-3.50, 3.81, 6.23, 6.87-6.97, 6.99, 7.85, 8.66.

EXAMPLE 23(7)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-[2-methoxy-1-(methoxymethyl)ethyl]-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.30 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.50, 7.82, 6.97, 6.89, 6.75, 6.16, 6.08,4.13-4.26, 3.80, 3.53-3.66, 3.39, 2.30.

EXAMPLE 23(8)2-[{5-[(2-chloro-4-methoxyphenyl)amino]-6-methylpyrazolo[1,5-a]pyrimidin-7-yl}(propyl)amino]ethanol

TLC: Rf 0.30 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.33-1.54, 2.32, 3.30-3.53, 3.53-3.76,3.82, 4.98-5.15, 6.26, 6.87-6.97, 6.99, 7.86, 8.58.

EXAMPLE 23(9)N⁷-butyl-N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.35 (hexane:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.81-0.91, 1.20-1.37, 1.37-1.56, 2.34,3.28-3.46, 3.81, 6.23, 6.87-6.95, 6.98, 7.86, 8.64.

EXAMPLE 23(10)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(2-methoxy-1-methylethyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.15 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.34, 2.30, 3.38, 3.48, 3.80, 4.07-4.25,5.88, 6.16, 6.75, 6.90, 6.97, 7.81, 8.50.

EXAMPLE 23(11)N⁵-(2-chloro-4-methoxyphenyl)-N⁷,N⁷-diethyl-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.28 (hexane:ethyl acetate=12:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.64, 7.85, 6.99, 6.87-6.96, 6.23, 3.81,3.46, 2.36, 1.05.

EXAMPLE 23(12)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-ethyl-6-methyl-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.32 (hexane:acetone=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.05, 1.39-1.56, 2.35, 3.29-3.40,3.40-3.52, 3.81, 6.23, 6.87-6.96, 6.98, 7.86, 8.63.

EXAMPLE 23(13)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-[(1R)-1-(methoxymethyl)propyl]-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.20 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.00, 1.52-1.89, 2.30, 3.35, 3.43-3.57, 3.80,3.86-4.03, 5.87, 6.16, 6.76, 6.89, 6.97, 7.81, 8.50.

EXAMPLE 23(14)N⁷-(sec-butyl)-N⁵-(2-chloro-4-methoxyphenyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.18 (hexane:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.50, 7.80, 6.97, 6.89, 6.75, 6.16, 5.76,3.82-3.94, 3.80, 2.30, 1.53-1.79, 1.30, 0.99.

EXAMPLE 23(15)N⁵-(2-chloro-4-methoxyphenyl)-6-methoxy-N⁷-(2-methoxyethyl)-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.45 (toluene:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.70, 7.85, 7.71, 6.98, 6.91, 6.20, 4.00,3.89, 3.81, 3.57-3.66, 3.51, 3.24, 1.51-1.68, 0.87.

EXAMPLE 23(16)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-[1-(methoxymethyl)butyl]-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.26 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.93, 1.32-1.83, 2.30, 3.34, 3.42-3.55, 3.80,3.96-4.10, 5.85, 6.16, 6.76, 6.90, 6.97, 7.81, 8.51.

EXAMPLE 23(17)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(3-methoxypropyl)-6-methyl-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.23 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.38-1.55, 1.64-1.80, 2.34, 3.23,3.28-3.43, 3.42-3.55, 3.81, 6.21, 6.83-6.95, 6.97, 7.84, 8.60.

EXAMPLE 23(18)N⁷-butyl-N⁵-(2-chloro-4-methoxyphenyl)-N⁷-ethyl-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.34 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.05, 1.20-1.52, 2.35, 3.28-3.53, 3.81,6.23, 6.86-6.96, 6.98, 7.85, 8.63.

EXAMPLE 23(19)N-(2-chloro-4-methoxyphenyl)-7-[(2S,4R)-4-methoxy-2-(methoxymethyl)-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.40 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.59, 7.85, 6.98, 6.91, 6.86, 6.22,4.74-4.86, 4.10-4.20, 4.00-4.10, 3.81, 3.38-3.45, 3.36, 3.17-3.31, 3.15,2.30-2.40, 2.29, 2.03-2.13.

EXAMPLE 23(20)N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷-propyl-N⁷-(2-pyridinylmethyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.30 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.85, 1.47-1.65, 2.27, 3.31-3.54, 3.81, 4.74,6.25, 6.84, 6.91, 6.97, 7.09-7.20, 7.34-7.45, 7.54-7.65, 7.91,8.50-8.56, 8.59.

EXAMPLE 23(21)7-(1-azepanyl)-N-(2-chloro-4-methoxyphenyl)-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.57 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.58, 7.86, 6.98, 6.91, 6.88, 6.23, 3.81,3.39-3.46, 2.37, 1.74-1.88.

EXAMPLE 23(22)N-(2-chloro-4-methoxyphenyl)-6-methyl-7-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.49 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.56, 7.85, 6.98, 6.91, 6.87, 6.24,3.97-4.03, 3.91-3.96, 3.81, 3.55-3.62, 2.38, 2.03-2.12.

EXAMPLE 23(23)N-(2-chloro-4-methoxyphenyl)-6-methyl-7-(4-methyl-1,4-diazepan-1-yl)pyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.31 (chloroform:methanol 10:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.56, 7.85, 6.98, 6.90, 6.86, 6.23, 3.81,3.49-3.62, 2.80-2.86, 2.75-2.80, 2.46, 2.37, 2.02-2.11.

EXAMPLE 23(24)N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷-propyl-N⁷-(1,3-thiazol-4-ylmethyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.49 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.74, 8.59, 7.90, 7.20, 6.97, 6.90, 6.85,6.24, 4.79, 3.80, 3.37-3.50, 2.24, 1.47-1.62, 0.87.

EXAMPLE 23(25)Methyl[{5-[(2-chloro-4-methoxyphenyl)amino]-6-methylpyrazolo[1,5-a]pyrimidin-7-yl}(ethyl)amino]acetate

TLC: Rf 0.30 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.14, 2.20, 3.58, 3.79, 4.03, 4.08, 6.34,6.81, 6.96, 7.82, 7.86, 10.62.

EXAMPLE 23(26)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(cyclopropylmethyl)-6-methoxy-N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.56 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): 6 8.71, 7.85, 7.70, 6.98, 6.91, 6.20, 3.91,3.81, 3.62-3.68, 3.61, 1.53-1.67, 0.98-1.15, 0.88, 0.40-0.49, 0.07-0.17.

EXAMPLE 23(27)N-(2-chloro-4-methoxyphenyl)-7-[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.40 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.61, 7.83, 6.98, 6.91, 6.88, 6.23,4.67-4.76, 3.81, 3.58-3.67, 3.35-3.44, 3.24, 3.18, 2.32, 2.26-2.37,2.01-2.13, 1.83-1.96.

EXAMPLE 23(28)N-(2-chloro-4-methoxyphenyl)-7-[(2R)-2-(methoxymethyl)-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.40 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.61, 7.83, 6.98, 6.84-6.94, 6.23, 4.66-4.77,3.81, 3.57-3.67, 3.34-3.45, 3.20-3.27, 3.18, 2.32, 2.26-2.41, 2.01-2.14,1.83-1.95.

EXAMPLE 23(29)N-(2-chloro-4-methoxyphenyl)-7-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.44 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.55, 7.84, 6.98, 6.91, 6.84, 6.21,3.89-4.02, 3.81, 3.31-3.46, 3.10-3.26, 2.32, 1.24.

EXAMPLE 23(30)N-(2-chloro-4-methoxyphenyl)-6-methyl-7-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]pyrimidine-5-amine

TLC- Rf 0.24 (chloroform: methanol=19:1);

¹H-NMR (300 MHz, CDCl₃): δ 2.31, 2.39, 2.52-2.74, 3.43-3.69, 3.80, 6.20,6.81, 6.90, 6.97, 7.83, 8.54.

EXAMPLE 23(31)7-(4-acetyl-1-piperazinyl)-N-(2-chloro-4-methoxyphenyl)-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.21 (hexane:ethyl acetate=1:3);

¹H-NMR (300 MHz, CDCl₃): δ 2.17, 2.35, 3.32-3.99, 3.81, 6.22, 6.86,6.91, 6.99, 7.83, 8.54.

EXAMPLE 23(32)N-(2-chloro-4-methoxyphenyl)-7-[(2S,4R)-2-(methoxymethyl)-4-methyl-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.18 (hexane:ethyl acetate=8:1);

¹H-NMR(300 MHz, CDCl₃): δ 1.14, 1.89-2.11, 2.31, 2.42-2.63, 2.97-3.10,3.18, 3.22, 3.69, 3.81, 4.67-4.87, 6.23, 6.87, 6.91, 6.98, 7.85, 8.60.

EXAMPLE 23(33)N-(2-chloro-4-methoxyphenyl)-7-[(2S,4R)-4-ethoxy-2-(ethoxymethyl)-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.20 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.94, 1.21, 1.99-2.14, 2.26-2.41, 2.29,3.16-3.34, 3.34-3.43, 3.43-3.62, 3.81, 4.03-4.14, 4.20-4.32, 4.66-4.81,6.22, 6.84, 6.91, 6.98, 7.84, 8.57.

EXAMPLE 23(34)N-(2-chloro-4-methoxyphenyl)-7-[(2S,4S)-2-(methoxymethyl)-4-fluoro-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.26 (hexane:ethyl acetate=12:1);

¹H-NMR (300 MHz, CDCl₃): δ 2.09-2.30, 2.40, 2.57-2.88, 3.23, 3.33-3.48,3.49-3.68, 3.71-3.94, 3.81, 4.43-4.60, 5.25-5.53, 6.25, 6.92, 6.95,6.99, 7.80, 8.62.

EXAMPLE 23(35)N-(2-chloro-4-methoxyphenyl)-7-[(2S,4S)-2-(methoxymethyl)-4-methyl-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.20 (toluene:ethyl acetate=19:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.15, 1.44-1.59, 2.27-2.42, 2.31, 2.46-2.67,3.15, 3.17-3.25, 3.25-3.47, 3.81, 4.93-5.06, 6.22, 6.86, 6.91, 6.98,7.84, 8.59.

EXAMPLE 23(36)N-(2-chloro-4-methoxyphenyl)-7-[(2S,4R)-4-ethyl-2-(methoxymethyl)-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.25 (toluene:ethyl acetate=19:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.96, 1.44-1.65, 1.95-2.09, 2.23-2.43, 2.31,3.03-3.14, 3.19, 3.20-3.29, 3.63-3.76, 3.81, 4.64-4.77, 6.23, 6.87,6.91, 6.98, 7.84, 8.60.

EXAMPLE 23(37)N-(2-chloro-4-methoxyphenyl)-7-[(2R,4S)-2-(methoxymethyl)-4-methyl-1-pyrrolidinyl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.19 (toluene:ethyl acetate=19:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.14, 1.93-2.08, 2.30, 2.41-2.63, 2.98-3.08,3.18, 3.23, 3.64-3.75, 3.81, 4.71-4.87, 6.23, 6.84-6.96, 6.98, 7.85,8.51-8.66.

EXAMPLE 23(38)N-(2-chloro-4-methoxyphenyl)-7-[(2S)-2-(methoxymethyl)-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-6-methylpyrazolo[1,5-a]pyrimidine-5-amine

TLC: Rf 0.19 (hexane:ethyl acetate=6:1);

¹H-NMR (300 MHz, CDCl₃): δ 2.42, 3.24, 3.43, 3.82, 4.57-4.70, 4.74-4.89,5.46-5.63, 6.28, 6.33-6.39, 6.93, 6.98, 7.00, 7.22-7.49, 7.86,8.58-8.70.

EXAMPLE 24(1)-EXAMPLE 24(4)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 3→Example 4, using a corresponding compoundprepared by the same procedure as a series of reactions of Example19→Example 20.

EXAMPLE 24(1)N⁵-(2-chloro-4-methoxyphenyl)-2,6-dimethyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3→Example 4,using 2,6-dimethyl-5,7-dichloropyrazolo[1,5-a]pyrimidine.

TLC: Rf 0.78 (hexane:ethyl acetate=6:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.85, 1.45, 2.30, 2.40, 3.33, 3.79, 5.99,6.83, 6.89, 6.96, 8.60.

EXAMPLE 24(2)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)-2,6-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of corresponding Example3→Example 4, using 2,6-dimethyl-5,7-dichloropyrazolo[1,5-a]pyrimidine.

TLC: Rf 0.42 (hexane:ethyl acetate=6:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.96, 1.65, 2.25, 2.38, 3.68, 3.78, 5.72,5.92, 6.67, 6.87, 6.95, 8.45.

EXAMPLE 24(3)N⁵-(2-chloro-4-methoxyphenyl)-2-ethyl-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of corresponding Example3→Example 4, using2-ethyl-5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine.

TLC: Rf 0.64 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.31, 1.46, 2.32, 2.77, 3.34, 3.80,6.03, 6.84, 6.90, 6.97, 8.62.

EXAMPLE 24(4)

5-[(2-chloro-4-methoxyphenyl)amino]-7-(dipropylamino)-6-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3→Example 4,using 3-cyano-5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine.

TLC: Rf 0.48 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.86, 1.41-1.55, 2.34, 3.27-3.43, 3.83,6.91-7.04, 7.18, 8.05, 8.77.

EXAMPLE 25N²⁻-(2-chloro-4-methoxyphenyl)-N²-ethyl-N⁴,N⁴-dipropyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 5, using acorresponding compound prepared in Example 4 and a corresponding halide.

TLC: Rf 0.42 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.72, 1.18, 1.43, 3.01, 3.68, 3.81, 4.10,4.77, 5.12, 6.82, 7.00, 7.14.

EXAMPLE 26N²-ethyl-N²-mesityl-N⁴,N⁴-dipropyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 4→Example 5,using a corresponding compound prepared in Example 3 and correspondinganiline.

TLC: Rf 0.16 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 0.70, 1.13, 1.39, 2.01, 2.23, 3.09, 3.74,4.57, 5.03, 6.87.

EXAMPLE 272-[(2-chloro-4-methoxyphenyl)(methyl)amino]-4-(dipropylamino)furo[3,4-d]pyrimidin-7(5H)-one

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3→Example4→Example 5, using 2,4-dichlorofuro[3,4-d]pyrimidin-7(5H)-one.

TLC: Rf 0.27 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.34-1.09, 1.14-1.61, 2.84-3.20, 3.47, 3.81,5.19-5.38, 6.83, 7.00, 7.17.

EXAMPLE 28(1)-EXAMPLE 28(11)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 5, using the compound prepared in Example 4(1)and a corresponding halide.

EXAMPLE 28(1)N²-(2-chloro-4-methoxyphenyl)-N²-ethyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.18 (hexane ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.72, 1.17, 1.42, 1.93, 2.70, 2.89, 3.17,3.80, 4.10, 6.81, 6.99, 7.14.

EXAMPLE 28(2)N²-(2-chloro-4-methoxyphenyl)-N²,N⁴,N⁴-tripropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.25 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.73, 0.90, 1.44, 1.60, 1.93, 2.69, 2.89,3.17, 3.58, 3.80, 4.01, 6.80, 6.98, 7.15.

EXAMPLE 28(3)N²-(2-chloro-4-methoxyphenyl)-N²-isopropyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.65 (hexane:tetrahydrofuran=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.70, 1.06, 1.34, 1.94, 2.72, 2.89, 3.12,3.81, 5.11, 6.80, 7.00, 7.10.

EXAMPLE 28(4)N²-aryl-N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.24 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.72, 1.43, 1.94, 2.70, 2.89, 3.17, 3.79,4.16, 4.82, 5.05, 6.02, 6.78, 6.98, 7.13.

EXAMPLE 28(5)N²-(2-chloro-4-methoxyphenyl)-N²-(2-methyl-2-propenyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.32 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.72, 1.42, 1.79, 1.94, 2.69, 2.89, 3.18,3.79, 3.98, 4.76, 4.80, 4.94, 6.77, 6.97, 7.17.

EXAMPLE 28(6)N²-(2-chloro-4-methoxyphenyl)-N²-isobutyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.23 (hexane ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.71, 0.94, 1.43, 1.90, 2.66, 2.89, 3.15,3.41, 3.80, 4.02, 6.80, 6.98, 7.18.

EXAMPLE 28(7)N-(2-chloro-4-methoxyphenyl)-N-[4-(dipropylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]acetamide

TLC: Rf 0.48 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.77, 1.38, 2.01, 2.46, 2.81, 2.96, 3.21,3.80, 6.81, 7.00, 7.19.

EXAMPLE 28(8)N-(2-chloro-4-methoxyphenyl)-N-[4-(dipropylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]methanesulfonamide

TLC: Rf 0.35 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.73, 1.39, 1.99, 2.78, 2.93, 3.16, 3.71,3.81, 6.85, 6.98, 7.36.

EXAMPLE 28(9)N²-(2-chloro-4-methoxyphenyl)-N²-(cyclopropylmethyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.18 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.02-0.19, 0.29-0.47, 0.57-0.84, 0.99-1.19,1.30-1.54, 1.85-2.04, 2.60-2.78, 2.83-2.96, 2.99-3.30, 3.30-3.51, 3.80,3.96-4.14, 6.80, 6.97, 7.23.

EXAMPLE 28(10)N²-(2-chloro-4-methoxyphenyl)-N²-(2-methoxyethyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

TLC: Rf 0.41 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.21, 6.97, 6.80, 4.23-4.39, 3.80, 3.51-3.78,3.31, 3.05-3.26, 2.85-2.93, 2.65-2.75, 1.87-2.01, 1.33-1.50, 0.66-0.79.

EXAMPLE 28(11)N²-ethyl-N²-mesityl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The title compound having the following-physical data was obtained bythe same procedure as a series of reactions of Example 3 (using2,4-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine)→Example 4 (using acorresponding aniline)→Example 5 (using a corresponding halide).

TLC: Rf 0.52 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 0.70, 1.11, 1.39, 1.89, 2.00, 2.23, 2.53,2.87, 3.18, 3.72, 6.86.

EXAMPLE 29(1)-EXAMPLE 29(10)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 5, using the compound prepared in Example 4(12)and a corresponding halide.

EXAMPLE 29(1)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-ethyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.20 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.76, 1.20, 1.51, 3.39, 3.78, 3.85, 4.19,4.72, 6.12, 6.90, 7.08, 7.20, 7.81.

EXAMPLE 29(2)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-(2-methyl-2-propenyl)-N⁷,N⁷-dipropylpyrazolo1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.25 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.77, 1.55, 1.82, 3.42, 3.84, 3.99, 4.80,5.07, 6.10, 6.86, 7.06, 7.22, 7.80.

EXAMPLE 29(3)N⁵-aryl-N⁵-(2-chloro-4-methoxyphenyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.21 (hexane:ethyl acetate=8:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 0.69, 1.46, 3.43, 3.80, 4.16, 4.73, 5.09,5.92, 6.00, 7.02, 7.22, 7.34, 7.81.

EXAMPLE 29(4)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-(cyclopropylmethyl)-N^(7,1),-dipropylpyrazolo1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.50 (hexane:ethyl acetate=6:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.06-0.20, 0.34-0.46, 0.76, 1.00-1.18,1.42-1.60, 3.33-3.56, 3.85, 4.03-4.23, 4.73, 6.11, 6.89, 7.06, 7.29,7.80.

EXAMPLE 29(5)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-[2-(dimethylamino)ethyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diaminetrihydrochloride

TLC: Rf 0.42 (chloroform:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.80, 1.53-1.72, 2.96, 3.05, 3.42-3.76, 3.86,3.88-3.95, 4.39-4.40, 4.53-4.66, 4.80-4.93, 6.90, 7.06, 7.10, 7.55,7.87.

EXAMPLE 29(6)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-[3-(dimethylamino)propyl]-N⁷,N⁷-propylpyrazolo[1,5-a]pyrimidine-5,7-diaminemethanesulfonate

TLC: Rf 0.38 (chloroform:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.78, 1.47-1.66, 2.16-2.40, 2.80, 2.93,3.21-3.35, 3.37-3.63, 3.73-3.93, 4.11-4.31, 4.51, 6.24-6.60, 7.00, 7.09,7.39, 7.83.

EXAMPLE 29(7)N⁵-(2-chloro-4-methoxyphenyl)-N⁵,N⁷,N⁷-tripropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.56 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.80, 7.20, 7.07, 6.89, 6.11, 4.66-4.75,3.95-4.23, 3.85, 3.51-3.72, 3.34-3.45, 1.42-1.70, 0.94, 0.76.

EXAMPLE 29(8)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-(2-methoxyethyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.57 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.81, 7.31, 7.05, 6.89, 6.11, 4.73,4.35-4.55, 3.84, 3.55-3.81, 3.40, 3.32, 1.43-1.59, 0.76.

EXAMPLE 29(9)ethyl{(2-chloro-4-methoxyphenyl)[7-(dipropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]amino}aceticacid

TLC: Rf 0.61 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.80, 7.62, 7.06, 6.88, 6.08, 5.11-5.33,4.83, 4.15-4.28, 3.75-3.98, 3.38-3.48, 1.46-1.60, 1.28, 0.77.

EXAMPLE 29(10)N⁵-(2-chloro-4-methoxyphenyl)-N⁵-(methoxymethyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine

TLC: Rf 0.57 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 7.80, 7.38, 7.18, 7.04, 6.00, 5.19, 4.92,3.84, 3.48-3.57, 3.37, 1.44-1.60, 0.76.

EXAMPLE 306-methyl-5-(5-methyl-2,3-dihydro-1H-indol-1-yl)-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

A compound prepared by the same procedure as a series of reactions ofExample 3 using 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine wasdissolved into N,N-dimethyimidazolidinone (2.5 mL). To the mixture ofthe solution and indoline (149 mg),tris(dibenzylideneacetone)dipalladium (34 mg), N,N-dimesitylimidazoliumhydrochloride (25 mg) and sodium hexadimethyldisilazide (275 mg) wereadded under argon gas atmosphere at room temperature. The mixture wasstirred for 1 hour at 100° C. under argon gas atmosphere. After thereaction mixture was cooled, a saturated aqueous solution of ammoniumchloride (2.0 mL) was added to stop the reaction to the mixture. Water(3.0 mL), hexane (4.0 mL) and ethyl acetate (1.0 mL) were added to themixture, and then it was stirred for 10 minutes. The organic layer wasseparated, and the water layer was extracted by a mixture of hexane andethyl acetate (4:1). The combined organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure.Tetrahydrofuran (2.0 mL) and pyridine (0.3 mL) were added to theresidue. And then a solution of phthalic acid anhydride oftetrahydrofuran (1.3 mL) was added to the mixture. The mixture wasstirred for 30 minutes at room temperature. The reaction mixture waspassed through trisamine resin supported by polystyrene, and after itwas washed three times with tetrahydrofuran, the solution wasconcentrated under reduced pressure. The residue was purified by columnchromatography (hexane:acetone=5:1) to give the title compound (136 mg)having the following physical data.

TLC: Rf 0.48 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.93, 7.04, 6.90, 6.48, 6.31, 4.11,3.38-3.59, 3.08, 2.29, 2.14, 1.47-1.66, 0.88.

EXAMPLE 315-(5-methyl-2,3-dihydro-1H-indol-1-yl)-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 30, using acompound prepared by the same procedure as a series of reactions ofExample 3 using 5,7-dichloropyrazolo[1,5-a]pyrimidine.

TLC: Rf 0.61 (toluene:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.98, 7.87, 6.92-7.07, 6.19, 5.66, 4.13,3.59-3.74, 3.15, 2.31, 1.61-1.79, 0.93.

EXAMPLE 31(1)5-(5-chloro-1H-indol-1-yl)-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 31, using acorresponding compound.

TLC: Rf 0.64 (toluene:ethyl acetate=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.23, 7.98, 7.69, 7.60, 7.25, 6.63, 6.43,6.02, 3.65-3.94, 1.67-1.90, 0.98.

EXAMPLE 32 imidazo[1,2-a]pyrimidin-5,7-diol

Under argon gas atmosphere, sodium (1.39 g) was added to ethanol (36 mL)by little and little, and the ethanol solution was stirred until sodiumwas solved completely. A solution of 2-aminoimidazole ½ hydrochloride(4.00 g) and diethyl malonate (4.6 mL) were dropped, successively, tothe above solution. The mixture was refluxed for 6 hours at 90° C. Afterthe reaction mixture was cooled to room temperature, it was concentratedunder reduced pressure. Water (50 mL) was added to the residue. Thesolution was acidified (pH=1) by adding 5N hydrochloric acid (10 mL)with stirring under an ice-bath. The precipitate was collected byfiltration under vacuum and dried under vacuum to give the titlecompound having the following physical data.

¹H-NMR (300 MHz, CDCl₃): δ 4.97, 7.33, 7.41, 10.39-12.49.

EXAMPLE 33 5,7-dichloroimidazo[1,2-a]pyrimidine

Under argon gas atmosphere, phosphoryl chloride (12.4 g) was dropped tothe compound prepared in Example 32 (680 mg). The mixture was stirredfor 4 hours at 100° C. After the reaction mixture was cooled, it wasconcentrated under reduced pressure. The obtained residue was dissolvedto an ice-water slowly. After the solution was nitrified by addingsodium bicarbonate, it was extracted twice with ethyl acetate. Theorganic layer was washed with water and normal saline solution, driedover magnesium sulfate, filtered and concentrated under reduced pressureto give the title compound (680 mg) having the following physical data.

TLC: Rf 0.63 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 7.05, 7.71, 7.86.

EXAMPLE 34N⁷-(2-chloro-4-methoxyphenyl)-N⁷-ethyl-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 3 using thecompound prepared in Example 33→Example 4→Example 5 using acorresponding halide.

TLC: Rf 0.23 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.80, 1.22, 1.36-1.59, 2.84-3.06, 3.75-3.86,3.86, 4.14-4.39, 5.02, 6.90, 7.08, 7.12, 7.19, 7.37.

EXAMPLE 34(1)-EXAMPLE 34(13)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 3 using the compound prepared in Example 33 or acorresponding compound→Example 4, or by the same procedure as a seriesof reactions of Example 3 using the compound prepared in Example 33 or acorresponding compound→Example 4→Example 5 using a corresponding halide.

EXAMPLE 34(1)N⁷-aryl-N⁷-(2-chloro-4-methoxyphenyl)-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.45 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.37, 7.17, 7.13, 7.06, 6.87, 5.98-6.14,4.91-5.15, 4.19, 3.85, 2.94-3.02, 1.40-1.55, 0.80.

EXAMPLE 34(2) N⁷-(2-chloro-4-methoxyphenyl)-N⁵,N⁵,N⁷-tripropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.44 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.37, 7.20, 7.12, 7.07, 6.90, 5.02,4.08-4.23, 3.86, 3.61-3.74, 2.92-3.02, 1.62-1.75, 1.40-1.56, 0.93, 0.80.

EXAMPLE 34(3)N⁷-(2-chloro-4-methoxyphenyl)-N⁷-(2-methoxyethyl)-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.36 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.38, 7.32, 7.12, 7.04, 6.90, 5.05,4.44-4.57, 3.70-3.93, 3.59-3.69, 3.31, 2.92-3.03, 1.40-1.56, 0.80.

EXAMPLE 34(4)N⁷-(2-chloro-4-methoxyphenyl)-6-methoxy-N⁵-(2-methoxyethyl)-N⁵-propylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.49 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 9.01, 7.79, 7.40, 7.35, 6.97, 6.90, 3.89,3.81, 3.48-3.60, 3.32-3.42, 3.29, 1.51-1.66, 0.89.

EXAMPLE 34(5)6-methoxy-N⁵,N⁵-dipropyl-N⁷-(2,4,5-trimethylphenyl)imidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.52 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.28, 7.38, 7.21, 7.04, 6.95, 3.82,3.22-3.33, 2.28, 2.21, 1.54-1.70, 0.90.

EXAMPLE 34(6)N⁷-(2-chloro-4-methoxyphenyl)-6-methoxy-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.50 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 9.00, 7.78, 7.40, 7.24, 6.97, 6.90, 3.86,3.81, 3.23-3.33, 1.54-1.69, 0.90.

EXAMPLE 34(7)N⁷-(2,4-dichlorophenyl)-6-methoxy-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.5 (ethyl acetate:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 9.19, 8.00, 7.45, 7.39, 7.30, 7.27, 3.86,3.24-3.39, 1.52-1.71, 0.90.

EXAMPLE 34(8)N⁷-(4-chloro-2-methylphenyl)-6-methoxy-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.51 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.70, 7.40, 7.21-7.26, 7.15-7.18, 3.84,3.25-3.33, 2.33, 1.55-1.69, 0.90.

EXAMPLE 34(9)4-{[5-(dipropylamino)-6-methoxyimidazo[1,2-a]pyrimidin-7-yl]amino}-3-ethylbenzonitrile

TLC: Rf 0.71 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 9.16, 7.55-7.62, 7.45-7.49, 7.28, 3.85,3.28-3.36, 2.72, 1.56-1.70, 1.36, 0.91.

EXAMPLE 34(10)6-methoxy-N⁷-(4-methoxy-2-methylphenyl)-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.42 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.28, 7.36, 7.20, 6.95, 6.74-6.85, 3.83,3.80, 3.22-3.33, 2.32, 1.54-1.70, 0.90.

EXAMPLE 34(11)N⁷-(2-ethyl-4-methylphenyl)-6-methoxy-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.32 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.45, 7.37, 7.21, 7.17, 7.08, 7.02, 3.83,3.21-3.34, 2.67, 2.33, 1.53-1.70, 1.29, 0.90.

EXAMPLE 34(12)N⁷-(4-chloro-2-ethylphenyl)-6-methoxy-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.41 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.68, 7.40, 7.20-7.26, 7.17, 3.84, 3.25-3.33,2.67, 1.54-1.70, 1.31, 0.90.

EXAMPLE 34(13)6-methoxy-N⁷-(4-methyl-2-vinylphenyl)-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

TLC: Rf 0.33 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.50, 7.38, 7.29, 7.21, 7.18-7.21, 7.15,6.88, 5.69, 5.43, 3.81, 3.23-3.33, 2.34, 1.54-1.69, 0.90.

EXAMPLE 35N⁷-mesityl-6-methyl-N⁵,N⁵-dipropylimidazo[1,2-a]pyrimidine-5,7-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 4, using acompound by the same procedure as a series of reactions of Example32→Example 33, and corresponding aniline.

TLC: Rf 0.21 (methylene chloride:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.89, 1.54, 2.19, 2.24, 2.29, 3.17, 5.84,6.90, 7.19, 7.28.

EXAMPLE 36 N-(2-chloro-4-methoxyphenyl)-N-methylguanidine

2-chloro-4-methoxyphenylmethylaniline (2.0 g) and cyanamide (490 mg)were suspended in water (12 mL). A concentrated hydrochloric acid (0.97mL) was added to the suspension at room temperature, and then themixture was stirred with heating for 9 hours at 90° C. After thereaction mixture was cooled, a solid was removed by filtration. Thefiltrate was concentrated. Ethyl acetate and methanol were added to theresidue. The produced solid was collected by filtration and dried undervacuum to give the title compound (1.4 g) having the following physicaldata.

TLC: Rf 0.03 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.46, 7.24, 7.04, 3.81, 3.17.

EXAMPLE 37N-(2-chloro-4-methoxyphenyl)-N-methyl-6-(methylsulfanyl)-1,3,5-triazine-2,4-diamine

To a suspension of the compound prepared in Example 36 (400 mg) andiminonitrile (233 mg) in water (1.6 mL), an aqueous solution ofpotassium hydroxide (KOH 180 mg, H₂O 1.6 mL) was added at 40° C. Themixture was stirred for 2 hours. After the reaction mixture was cooledto room temperature, a produced solid was collected by filtration, anddried under vacuum. The solid was dissolved in hexane/ethyl acetate(1/1), and it was purified by column chromatography (hexane:ethylacetate=1:1) to give the title compound (360 mg) having the followingphysical data.

TLC: Rf 0.47 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.27, 7.08, 6.94, 6.50, 3.81, 3.28,2.09-2.41.

EXAMPLE 38N-(2-chloro-4-methoxyphenyl)-N-methyl-4-(methylsulfanyl)imidazo[1,2-a][1,3,5]triazine-2-amine

Water (0.07 mL) and hydrobromic acid (0.07 mL) were added tobromoacetaldehyde dimethyl acetal (291 mg) at room temperature, and themixture was refluxed with heating for 30 minutes. After the reactionmixture was cooled, dimethoxyethane (1.0 mL) was added to the mixture.And it was neutralized by sodium bicarbonate. The solution was washedwith dimethoxyethane and filtrated. To the filtrate, the compoundprepared in Example 37 (360 mg) was added at room temperature. Themixture was refluxed with heating for 3.5 hours. After the reactionmixture was cooled, it was concentrated under reduced pressure. Theobtained residue was purified by column chromatography (hexane:ethylacetate=50:50, hexane:ethyl acetate=0:100,dichloromethane:methanol=20:1) to give the title compound (50 mg) havingthe following physical data.

TLC: Rf 0.21 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 7.35, 7.20, 7.09, 7.01, 6.85, 3.84, 3.48,2.22.

EXAMPLE 39N²-(2-chloro-4-methoxyphenyl)-N²-methyl-N⁴,N⁴-dipropylimidazo[1,2-a][1,3,5]triazine-2,4-diamine

3-Aminopentane (1.0 mL) was added to the compound prepared in Example 38(49 mg). The mixture was refluxed with heating for 10 hours. After thereaction mixture was cooled, it was concentrated under reduced pressure.The obtained residue was purified by column chromatography by 100% ethylacetate to give the title compound (22 mg) having the following physicaldata.

TLC: Rf 0.25 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.74, 1.53, 3.21, 3.42, 3.80, 6.81, 6.97,7.07, 7.15, 7.24.

EXAMPLE 40N²-(2-chloro-4-methoxyphenyl)-N⁴-(1-ethylpropyl)-N²-methylthieno[3,2-d]pyrimidine-2,4-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 4 using2-ethylthiothieno[3,2-d]pyrimidin-4-one (it was described in JP3-17083)→Example 5→Example 3 using a corresponding amine.

TLC: Rf 0.18 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.80, 1.45, 3.44, 3.67, 3.83, 4.26, 6.84,7.01, 7.22, 7.51.

EXAMPLE 40(1)N²-(2-chloro-4-methoxyphenyl)-N²-methyl-N⁴,N⁴-dipropylthieno[3,2-d]pyrimidine-2,4-diamine

TLC: Rf 0.36 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.77, 1.50, 3.30, 3.44, 3.81, 6.83, 7.00,7.22, 7.54.

EXAMPLE 41N²-(2-chloro-4-methoxyphenyl)-N⁴-(1-ethylpropyl)-N²-methylthieno[2,3-d]pyrimidine-2,4-diamine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 4 using2-ethylthiothieno[2,3-d]pyrimidin-4-one (it was described in U.S. Pat.No. 4,146,716)→Example 5→Example 3 using a corresponding amine.

TLC: Rf 0.24 (hexane:ethyl acetate=6:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.78, 1.43, 3.43, 3.63, 3.83, 4.54, 6.83,6.91, 7.00, 7.21.

EXAMPLE 42

Ethyl4-(dipropylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-carboxylate

Under argon gas atmosphere, to a solution of the compound prepared by hesame procedure as a series of reactions of Example 3 using2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, in anhydrousethanol (1.4 mL) and dimethylformamide (0.7 mL), palladium acetate (8.8mg), diphenylphosphinoferrocene (22 g) and potassium carbonate (89 mg)were added at room temperature. After carbon dioxide gas displacement,the mixture was refluxed with heating for 1 hour. After the reactionmixture was cooled, a saturated aqueous solution of ammonium chloridewas added to stop a reaction. The mixture was extracted with ethylacetate. The organic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (hexane:ethyl acetate=1:1) to give the title compound (80mg) having the following physical data.

TLC: Rf 0.26 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 4.34-4.57, 3.36-3.69, 3.06, 2.94, 1.93-2.22,1.51-1.78, 1.35-1.52, 0.74-1.08.

EXAMPLE 43(2-chloro-4-methoxyphenyl)[4-(dipropylarino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]methanone

To a solution of the 3-chloro-4-bromoanisol (1.0 mg) in tetrahydrofuran(2.3 mL), isopropyl magnesium bromide (2.3 mL, 2.0 M tetrahydrofuransolution) was dropped at room temperature. The mixture was stirred for 2hours. The solution was added to a solution of the compound (190 mg)prepared in Example 42 in tetrahydrofuran (3.0 mL) at −30° C. Themixture was stirred for 30 minutes at −10° C. A saturated aqueoussolution of ammonium chloride was added to the reaction mixture to stopthe reaction. The mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was purified by column chromatography(hexane:acetone=2:1) to give the title compound (84.2 mg) having thefollowing physical data.

TLC: Rf 0.27 (hexane:acetone=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.76, 1.42-1.58, 1.95-2.18, 2.96, 3.06,3.22-3.40, 3.84, 6.85, 6.90, 7.55.

EXAMPLE 44 1-(2-chloro-4-methoxyphenyl)cyclopropanecarbonitrile

To a suspension of sodium hydride (1.0 g) in dimethylformamide (16.0mL), a solution of 2-chloro-4-methoxyphenylacetonitrile (2.0 g) indimethylformamide (10.0 mL) was dropped at 0° C. The mixture was stirredfor 1 hour at room temperature. To the reaction mixture,1,2-dibromoethane (1.1 mL) was dropped at 0° C. The mixture was stirredfor 20 hours at room temperature. The reaction mixture was cooled to 0°C., and water was added to stop a reaction to the reaction mixture. Themixture was extracted three times with a mixture of hexane and ethylacetate (4:1). The combined organic layer was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedresidue was purified by column chromatography (hexane:ethyl acetate=8:1,hexane:ethyl acetate=4:1) to give the title compound having thefollowing physical data.

TLC: Rf 0.35 (hexane:ethyl acetate=4:1);

¹H-NMR(300 MHz, CHCl₃-D): δ 7.25, 6.97, 6.78, 3.80, 1.60-1.80,1.17-1.40.

EXAMPLE 45 1-(2-chloro-4-methoxyphenyl)cyclopropanimidocarboxylic acidamide

To a suspension of ammonium chloride (433 mL) in anhydrous toluene (4.0mL), trimethyl aluminumi (3 mL, 2.0 M toluene solution) was added underice-bath. The mixture was stirred for 2 hours at room temperature. Tothe mixture, a solution of the compound (800 mg) prepared in Example 44in toluene (3.8 mL) was added. The mixture was stirred for 2 days at 80°C. After the reaction mixture was cooled, it was poured into asuspension of silica gel (3.0 g) in chloroform (10 mL) slowly, andstirred for 10 minutes. The reaction mixture was filtered through celiteand the filtrate was concentrated under reduced pressure. To theresidue, 2N hydrochloric acid (5.0 mL) was added, and it was decantedwith diethyl ether. The water layer was neutralized by adding 5N aqueoussolution of sodium hydroxide (3.0 mL), and then sodium chloride wasadded. The solution was extracted with three times with tetrahydrofuran.The organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduce pressure to give the title compound (740 mg)having the following physical data.

TLC: Rf 0.17 (methylene chloride:methanol=9:1);

¹H-NMR (300 MHz, CHCl₃-D): δ 7.38, 7.04, 6.90, 3.76, 1.39-1.74,0.91-1.24.

EXAMPLE 462-[1-(2-chloro-4-methoxyphenyl)cyclopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol

Sodium hydroxide (163 mg) was dissolved in ethanol (3.7 mL) at roomtemperature, and the compound (640 mg) prepared in Example 45 and ethyl2-oxycyclopentanecarbonate (0.78 mL) were added to the solution. Themixture was refluxed with heating for 5 hours. After the reactionmixture was cooled, water was added to the mixture and the then themixture was neutralized by adding 1N hydrochloric acid. The mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. Hexane wasadded to the obtained residue, and the obtained solid was collected byfiltration and dried to give the title compound (630 mg) having thefollowing physical data.

TLC: Rf 0.43 (hexane:ethyl acetate=1:2);

hu 1H-NMR (300 MHz, CHCl₃-D): δ 7.34, 7.02, 6.87, 3.85, 2.64-2.96,1.98-2.17, 1.81-1.96, 1.30-1.43.

EXAMPLE 474-chloro-2-[1-(2-chloro-4-methoxyphenyl)cyclopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

To the compound prepared in Example 46 (600 mg), phosphoryl chloride(2.0 mL) was added. The mixture was refluxed with heating for 20minutes. After the reaction mixture was cooled, ‘it was’ poured into anice-bath. The mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium bicarbonateand a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the title compound (660 mg) having the following physical data.

TLC: Rf 0.57 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CHCl₃-D): δ 7.30, 6.95, 6.80, 3.81, 2.77-3.01,1.98-2.19, 1.74-1.88, 1.27-1.43.

EXAMPLE 482-[1-(2-chloro-4-methoxyphenyl)cyclopropyl]-N,N-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

A solution of the compound prepared in Example 47 (300 mg) in3-aminopentane (1.0 mL) was refluxed with heating for 24 hours. Afterthe reaction mixture was cooled, it was poured into water. The mixturewas extracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedresidue was purified by column chromatography (hexane:ethyl acetate=5:1)to give the title compound (152 mg) having the following physical data.

TLC: Rf 0.35 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CHCl₃-D): δ 0.71, 1.21, 1.39, 1.74, 1.94, 2.74, 2.92,3.15, 3.78, 6.75, 6.91, 7.27.

EXAMPLE 49 methyl 4-(2-chloro-4-methoxyphenyl)-2-methyl-3-oxobutanoate

Under argon gas atmosphere, a solution of zinc powder (1.81 g) intetrahydrofuran (16 mL) was refluxed. To the mixture, methyl2-bromopropionate (4 drops) was dropped, and2-chloro-4-methoxyphenylacetnitrile (1.0 g) was added and then methyl2-bromopropionate (2.46 mL) was dropped. The mixture was refluxed for 10minutes. After the reaction mixture was cooled, it was diluted withtetrahydrofuran. A 50% aqueous solution of potassium carbonate was addedto the diluted solution, and the mixture was stirred for 30 minutes. Thereaction mixture was filtered, and washed with tetrahydrofuran. 2Nhydrochloric acid (6 mL) was added to the filtrate. The mixture wasstirred for 30 minutes and concentrated. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=92:8→71:29) togive the title compound (1.22 g) having the following physical data.

TLC: Rf 0.55 (hexane:ethyl acetate=2:1).

EXAMPLE 505-(2-chloro-4-methoxybenzyl)-6-methylpyrazolo[1,5-a]pyrimidin-7-ol

A solution of 3-aminopyrazole (272 mg) and the compound of Example 49(886 mg) in acetic acid (4.0 mL) was refluxed for 2 hours. After thereaction mixture was cooled, it was diluted with ethyl acetate. Theproduct was collected by filtration to give the title compound (421 mg)having the following physical data.

TLC: Rf 0.52 (chloroform:methanol=10:1).

EXAMPLE 517-chloro-5-(2-chloro-4-methoxybenzyl)-6-methylpyrazolo[1,5-a]pyrimidine

Under argon gas atmosphere, to a solution of the compound prepared inExample 50 (511 mg) in toluene (5.0 mL), diethylaniline (270 μL) andphosphoryl chloride (776 mg) were added. The mixture was refluxed for2.5, hours. After the reaction mixture was cooled, it was poured into anice-water and a saturated aqueous solution of sodium bicarbonate wasadded to the solution. The solution was extracted with ethyl acetate.The extracted solution was washed with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=92: 8→71:29) to give the title compound(528 mg) having the following physical data.

TLC: Rf 0.54 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CHCl₃-D): δ 8.12, 6.98, 6.94, 6.72, 6.68, 4.28, 3.79,2.35.

EXAMPLE 525-(2-chloro-4-methoxybenzyl)-6-methyl-N-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidine-7-amine

The title compound (175 mg) having the following physical data wasobtained by the same procedure as a series of reactions of Example 3using the compound prepared in Example 51 (150 mg) and 3-aminopentane(220 μL).

TLC: Rf 0.57 (hexane:ethyl acetate=2:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.95, 6.96, 6.89, 6.67, 6.44, 6.02, 4.20,3.82-3.95, 3.77, 2.16, 1.49-1.72, 0.93.

EXAMPLE 52(1)-EXAMPLE 52(4)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 49→Example 50→Example 51→Example 52, using acorresponding compound.

EXAMPLE 52(1)5-[1-(2-chloro-4-methoxyphenyl)cyclopropyl]-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

TLC: Rf 0.59 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.78, 1.25-1.33, 1.46-1.65, 1.85-1.94,3.42-3.58, 3.83, 5.39, 6.33, 6.85, 6.99, 7.38, 7.91.

EXAMPLE 52(2)5-(2-chloro-4-methoxybenzyl)-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

TLC: Rf 0.64 (hexane:ethyl acetate=3:1);

¹H-NMR (300 MHz, CDCl₃): δ 8.01, 6.97, 6.91, 6.69, 6.54, 4.22, 3.78,3.32-3.42, 2.17, 1.37-1.54, 0.75-0.87.

EXAMPLE 52(3)5-mesitylmethyl-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

TLC: Rf 0.64 (hexane:ethyl acetate=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.84, 1.40-1.55, 2.18, 2.30, 2.36, 3.32-3.42,4.09, 6.40, 6.89, 7.92.

EXAMPLE 52(4)5-(2,4-dichlorobenzyl)-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

TLC: Rf 0.63 (hexane:ethyl acetate=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.82, 1.38-1.55, 2.18, 3.29-3.48, 4.24, 6.53,6.97, 7.13, 7.43, 8.01.

EXAMPLE 535-(4-chloro-2-methylphenoxy)-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

To a solution of5-chloro-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine (150 mg)in dimethylformamide (3.0 mL), 4-chloro-o-cresol (96 mg) and cesiumcarbonate (276 mg) were added. The mixture was stirred for 5 hours at80° C. The reaction mixture was diluted with ethyl acetate. The dilutedsolution was washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=100:0→95:5) to give the title compound(190 mg) having the following physical data.

TLC: Rf 0.60 (hexane:ethyl acetate=7:1);

¹H-NMR(300 MHz, CDCl₃): δ 7.87, 7.24-7.28, 7.18-7.24, 7.07, 6.21,3.40-3.48, 2.33, 2.16, 1.46-1.61, 0.88.

EXAMPLE 53(1)-EXAMPLE 53(2)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 53, using a corresponding compound.

EXAMPLE 53(1)5-(4-ethyl-2-methoxyphenoxy)-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

The title compound having the following physical data was obtained bythe same procedure as a series of reactions of Example 53, using acorresponding compound.

TLC: Rf 0.36 (hexane:ethyl acetate=7:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87, 1.28, 1.45-1.60, 2.35, 2.69, 3.37-3.47,3.75, 6.20, 6.80-6.87, 7.07, 7.85.

EXAMPLE 53(2)5-[(3-chloro-1,1′-biphenyl-4-yl)oxy]-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine

TLC: Rf 0.40 (hexane:ethyl acetate=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88, 1.48-1.62, 2.39, 3.42-3.50, 6.24,7.32-7.41, 7.41-7.50, 7.50-7.64, 7.70, 7.88.

Pharmacological Activities

The compound of the present invention of formula (I) possesses CRFreceptor antagonistic activity, for example, such an effect of thecompound of the present invention was confirmed by following tests.

Experiment 1

Binding Assay:

<Cell Membrane Preparation>

After the cell line expressing human CRF receptor 1 (expressed cellline: CHO-K1 cells) was cultured to reached confluence, the cells wereharvested with a scraper. Harvested cells were washed twice with PBSbefore being suspended in binding assay buffer (Tris-HCl (50 mM, pH7.0), EDTA (2 mM, pH8.0), MgCl₂ (10 mM)) cooled by ice. Suspended cellswere homogenized with a Downs-type homogenizer and subjected tocentrifugationd at 10,000 g to collect the membrane fraction. Theharvested cell membrane fraction was re-suspended with a small quantityof the binding assay buffer, and further diluted with said buffer to 1mg/mL. The membrane fraction thus obtained was used for binding assay.

<Binding Assay>

Fifty μL of [¹²⁵I] h/r CRF prepared to 0.5 nM with binding assay bufferwas added to siliconized 1.5 mL tubes. 1 μL of compounds diluted inappropriate multiples, DMSO (for total binding use), or h/r CRF solution(100 μM for the non-specific binding use), respectively, added to thetubes. Samples of 50 μL each of the membrane fraction preparation wereadded to the tubes to initiate the reaction (final concentration of[¹²⁵I] h/r CRF: 0.25 nM), then the mixtures were incubated for 2 hoursat room temperature. After termination of the reaction, tubes weresubjected to centrifugation at 20,000 g to collect the membranefraction. The supernatant was discarded, and the pellet was rinsed twicewith cooled PBS (−) containing 0.01% Triton X-100. Radioactivity valuesof the respective tubes were measured with a γ-counter.

The specific binding was derived by subtracting the non-specific bindingvalue from the each binding value.

The results indicated that these compounds of the present inventionexhibited potent affinity on CRF receptor (IC₅₀: <1 μM).

Experiment 2

Receptor Antagonistic Activity (Cyclic AMP Assay):

The cell line expressing human CRF1 receptor was cultured using 10%bovine embryo serum and 1% F-12 nutrient mixture containing antibioticsand antifungal under 37° C., 5% carbonic anhydride, 95% air. On the daybefore a measurement of cyclic AMP, the cell seed to 96-well plate to be1×10⁴ cell/well. On the measurement day, the cell was washed twice withF-12 nutrient mixture, and F-12 nutrient mixture/1 mM3-isobutyl-1-methylxanthin (assay medium) (178 μL) was added to eachwell. After they were incubated for 10 minutes at 37° C., variousconcentrated solution of the test compound (2 μL) was added, or DMSO (2μL) to CRF group and blank group was added. After they were incubatedfor 15 minutes at 37° C., 10 nM assay medium containing human/rat CRF(20 μL) was added to the test compound group and CRF group. To blankgroup, assay medium containing 0.00001% acetic acid (20 μL) was added.Furthermore, they were incubated for 15 minutes at 37° C. A supernatantwas removed, and the reaction was stopped by cooling using ice. Also,all reaction was carried out by 3 wells. The cumulative dosage ofintracellular cyclic AMP was measured by Biotrak enzyme immunoassaysystem (Amershain Biosciences). The cumulative dosage of cyclic AMP wasderived by subtracting the average value of 3 wells of blank group fromthe average value of 3 wells. The IC₅₀ values calculated by nonlinearregression analysis with logarithm concentrate of the compound as theautonomous variable and cyclic AMP cumulative dosage as an inducedvariable

The results indicated that compound (1) exhibited potent antagonistactivity on CRF receptor (IC₅₀: <1 μM).

FORMULATION EXAMPLE 1

The following components were admixed in conventional method and punchedout to obtain 10,000 tablets each containing 10 mg of active ingredient.N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-5,7- 100 gdihydrofuro[3,4-d]pyrimidine-2,4-diamine Carboxymethylcellulose calcium(disintegrating agent) 20 g Magnesium stearate (lubricating agent) 10 gMicrocrystalline cellulose 870 g

FORMULATION EXAMPLE 2

The following components were admixed in conventional method. Thesolution was sterilized in conventional manner, filtered through dustremoval equipment, placed 5 ml portions into ampoules and sterilized byautoclave to obtain 10,000 ampoules each containing 20 mg of the activeingredient. N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-5,7- 200 gdihydrofuro[3,4-d]pyrimidine-2,4-diamine mannitol ¥ 20 g distilled water50 L

INDUSTRIAL APPLICABILITY

The compound of the present invention is useful, in order to bind a CRFreceptor and show a CRF receptor antagonistic activity, for theprevention and/or treatment of CRF mediated diseases, for example,neuropsychiatric disorders, digestive diseases.

1. A CRF antagonist comprising, as an active ingredient, a compoundrepresented by formula (I):

wherein ring A represents a 5- or 6-membered monocyclic ring which maybe substituted with 1 to 3 substituents selected from a halogen atom,CF₃, OCF₃, hydroxyl, mercapto, carboxyl, (C1-6 alkoxy)carbonyl,carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may be substitutedwith 1 to 3 substituents selected from a halogen atom, CF₃ and hydroxyl;ring B represents a 5- to 7-membered monocyclic unsaturated heterocyclicring which may contain 1 or 2 hetero atoms selected from a nitrogenatom, an oxygen atom and/or a sulfur atom which may be oxidized, otherthan the nitrogen atom, W¹ and W² and which may be further substituted;W¹ and W² each independently represents a carbon atom or a nitrogenatom; Z represents —NR³—, in which R³ represents a hydrogen atom, C1-6alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted,—CO—(C1-6 alkyl which may be substituted), —SO₂—(C1-6 alkyl which may besubstituted), an oxygen atom, a sulfur atom which may be oxidized, or—CR⁴R⁵—, in which R⁴ and R⁵ each independently represents a hydrogenatom, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may besubstituted, or R⁴ and R⁵ may be taken together to represent (i) oxo,(ii) C2-5 alkylene in which one carbon atom may be substituted with oneoxygen atom, nitrogen atom or sulfur atom which may be oxidized, whereinthe C2-5 alkylene may be substituted with a substituent(s), or (iii)C1-6 alkylidene which may be substituted; R¹ represents: (i) C1-15alkyl, C2-15 alkenyl or C2-15 alkynyl which each may be substituted,(ii) amino which may be protected, (iii) hydroxyl which may beprotected, (iv) mercapto which may be protected, (v) —S(O)_(n)R⁶, inwhich n represents 1 or 2, and R⁶ represents (a) C1-15 alkyl, C2-15alkenyl or C2-15 alkynyl which each may be substituted or (b) a cyclicgroup which may be substituted, (vi) —COR⁷, in which R⁷ represents (a) ahydrogen atom, (b) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl whicheach may be substituted, (c) hydroxyl which may be protected, (d) aminowhich may be protected, or (e) a cyclic group which may be substituted,or (vii) a cyclic group which may be substituted; R² represents anunsaturated cyclic group which may be substituted, in which thesubstituent may be taken together with R³ to form C2-5 alkylene whichmay be substituted, a salt thereof, an N-oxide thereof, a solvatethereof or a prodrug thereof.
 2. A compound represented by formula(I-A):

wherein

represents a ring selected from (1) cyclic group 1:

(2) cyclic group 2:

and ring A may be substituted with 1 to 3 substituents selected from ahalogen atom, CF₃, OCF₃, hydroxyl, mercapto, carboxyl, (C1-6alkoxy)carbonyl, carbamoyl, nitro, cyano, oxo, and C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each maysubstituted with 1 to 3 substituents selected from a halogen atom, CF₃and hydroxyl, and ring B may be further substituted; R¹ represents: (i)C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which each may besubstituted, (ii) amino which may be protected, (iii) hydroxyl which maybe protected, (iv) mercapto which may be protected, (v) —S(O)_(n)R⁶, inwhich n represents 1 or 2, and R⁶ represents (a) C1-15 alkyl, C2-15alkenyl or C2-15 alkynyl which each may be substituted, or (b) a cyclicring which may be substituted, (vi) —COR⁷, in which R⁷ represents (a) ahydrogen atom, (b) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl whicheach may be substituted, (c) hydroxyl which may be protected, (d) aminowhich may be protected, or (e) a cyclic group which may be substitute,or (vii) a cyclic group which may be substituted; R^(1a) represents: (i)C1-15 alkyl or C2-15 alkenyl which may be substituted with substituentgroup 1, (ii) NR⁸R⁹, in which R⁸ represents (a) a hydrogen atom or (b)C1-15 alkyl or C2-15 alkenyl which each may be substituted withsubstituent group 1, and R⁹ represents (a) a hydrogen atom, (b) C1-15alkyl or C2-15 alkenyl substituted with substituent group 1, (c) —COR¹⁰,in which R¹⁰ represents (aa) a hydrogen atom or (bb) C1-15 alkyl orC2-15 alkenyl which each may be substituted with substituent group 1,(d) —COOR¹⁰, in which R¹⁰ has the same meaning as described above, or(e) —CON(R⁸)₂, in which R⁸s each independently has the same meaning asdescribed above, (iii) OR¹⁰, in which R¹⁰ has the same meaning describedabove, (iv) SR¹⁰, in which R¹⁰ has the same meaning described above, (v)S(O)_(n)R¹¹, in which n represents 1 or 2, and R¹¹ represents C1-15alkyl or C2-15 alkenyl which each may be substituted with substituentgroup 1, or (vi) COR¹², in which R¹² represents (a) a hydrogen atom, (b)C1-15 alkyl or C2-15 alkenyl which each may be substituted withsubstituent group 1, (c) —OR¹⁰, in which R¹⁰ has the same meaning asdescribed above, or (d) —NR⁸R⁹, in which R⁸ and R⁹ have the samemeanings as described above; the substituent group 1 represents (1) ahalogen atom, (2) CF₃, (3) OCF₃, (4) cyano, (5) nitro, (6) hydroxyl, (7)C1-6 alkoxy, (8) carboxyl, (9) (C1-6 alkoxy)carbonyl, (10) C1-5 acyl,(11) carbamoyl in which a nitrogen atom may be protected with 1 or 2 ofC1-6 alkyl, (12) C1-6 alkylthio, (13) C1-6 alkylsulfonyl, or (14)NR¹³R¹⁴, in which R¹³ represents (a) a hydrogen atom, (b) C1-6 alkyl, or(c) C2-6 alkenyl, and R¹⁴ represents (a) a hydrogen atom, (b) C1-6alkyl, (c) C2-6 alkenyl, (d) —COR¹⁵, in which R¹⁵ represents (aa) ahydrogen atom, (bb) C1-6 alkyl or (cc) C2-6 alkenyl, (e) —COOR¹⁵, inwhich R¹⁵ has the same meaning as described above, or (f) —CON(R¹⁶)₂, inwhich R¹⁶s each independently represents a hydrogen atom or C1-6 alkyl;Z^(a) represents —NR³—, in which R³ represents a hydrogen atom, C1-6alkyl, C2-6 alkenyl or C2-6 alkynyl which each may be substituted,—CO—(C1-6 alkyl which may be substituted), —SO₂—(C1-6 alkyl which may besubstituted), an oxygen atom, a sulfur atom which may be oxidized, or—CR⁴R⁵—, in which R⁴ and R⁵ each independently represents a hydrogenatom, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which each may besubstituted, or R⁴ and R⁵ may be taken together to represent (i) oxo,(ii) C2-5 alkylene in which one carbon atom may be substituted with oneoxygen atom, nitrogen atom or sulfur atom which may be oxidized, whereinthe C2-5 alkylene may be substituted with a substituent(s), or (iii)C1-6 alkylidene which may be substituted; R^(2a) represents (1) a C5-12monocyclic or bicyclic unsaturated carbocyclic ring which may besubstituted, (2) pyridine which may be substituted, (3) a bicyclicheterocyclic ring which may be substituted, in which benzene and a 5- or6-membered monocyclic heterocyclic ring are fused, (4) a bicyclicheterocyclic ring which may be substituted, in which a pyridine ring anda C5-6 monocyclic carbocyclic ring are fused, or (5) a bicyclicheterocyclic ring which may be substituted, in which a pyridine ring anda 5- or 6-membered monocyclic heterocyclic ring are fused, a saltthereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 3.The compound according to claim 2,

wherein all symbols have the same meanings as described in claim 2, asalt thereof, an N-oxide thereof, a solvate thereof or a prodrugthereof.
 4. The compound according to claim 2, wherein R¹ is amino whichmay be protected, or R^(1a) is NR⁸R⁹, in which R⁸ and R⁹ have the samemeanings as described in the claim 2, a salt thereof, an N-oxidethereof, a solvate thereof or a prodrug thereof.
 5. The compoundaccording to claim 2, wherein Z^(a) is —NR³—, in which R³ has the samemeaning as described in claim 2, a salt thereof, an N-oxide thereof, asolvate thereof or a prodrug thereof.
 6. The compound according to claim2, wherein Z^(a) is —CR^(4b)R^(5b)—, in which R^(4b) and R^(5b) aretaken together to represent C2-5 alkylene in which one carbon atom maybe substituted with one oxygen atom, nitrogen atom or sulfur atom whichmay be oxidized, wherein the C2-5 alkylene may be substituted with asubstituent(s), a salt thereof, an N-oxide thereof, a solvate thereof ora prodrug thereof.
 7. The compound according to claim 2, which isrepresented by formula (I-A-3):

R^(1-A) represents amino which may be protected with 1 or 2 of C1-15alkyl which may be substituted; G^(a1)s each independently represents ahydrogen atom, a halogen atom, CF₃, OCF₃, hydroxyl, mercapto, carboxyl,(C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, or C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6 alkylthio which each may besubstituted with 1 or 2 substituents selected from a halogen atom, CF₃and hydroxyl; G² represents a hydrogen atom, C1-15 alkyl, C2-15 alkenylor C2-15 alkynyl which may be substituted, hydroxyl which may beprotected, cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl,a halogen atom, CF₃, or cyano; and other symbols have the same meaningsas in claim 2, a salt thereof, an N-oxide thereof, a solvate thereof ora prodrug thereof.
 8. The compound according to claim 2, which isrepresented by formula (I-A-4):

R^(1a-A) represents NR^(8A)R^(9A), in which one of R^(8A) and R^(9A)represents C1-15 alkyl which may be substituted with the substituentgroup 1 and another represents a hydrogen atom or C1-15 alkyl which maybe substituted with the substituent group 1, wherein the substituentgroup 1 has the same meaning as in claim 2; G^(a2)s each independentlyrepresents a hydrogen atom, a halogen atom, CF₃, OCF₃, hydroxyl,mercapto, carboxyl, (C1-6 alkoxy)carbonyl, carbamoyl, nitro, cyano, oxy,oxo, or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy or C1-6alkylthio which each may be substituted with 1 or 2 substituentsselected from a halogen atom, CF₃ and hydroxyl; and other symbols havethe same meanings as described in claim 2 or 7, a salt thereof, anN-oxide thereof, a solvate thereof or a prodrug thereof.
 9. The compoundaccording to claim 2, which is: (1)N⁵-(2-chloro-4-methoxyphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,(2)N⁵-(2-chloro-4-methoxyphenyl)-N⁷-(1-ethylpropyl)-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine,(3)N⁵-(2-chloro-4-methoxyphenyl)-6-ethyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,(4)N²-(2-chloro-4-methoxyphenyl)-N²-ethyl-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,(5)N⁵-(2-chloro-4-methoxyphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,(6)N²-allyl-N²-(2-chloro-4-methoxyphenyl)-N⁴,N⁴-dipropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,(7)6-methyl-N⁵-[2-methyl-4-(trifluoromethoxy)phenyl]-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,(8)N⁷-butyl-N⁵-(2-chloro-4-methoxyphenyl)-N⁷-ethyl-6-methylpyrazolo[1,5-a]pyrimidine-5,7-diamine,(9)N⁵-(2-ethyl-4-methylphenyl)-6-methyl-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,(10)6-methoxy-N⁵-(4-methyl-2-vinylphenyl)-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine,or (11)N⁵-(2-ethyl-4-methylphenyl)-6-methoxy-N⁷,N⁷-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine.10. A pharmaceutical composition comprising, as an active ingredient,the compound represented by formula (I-A) according to claim 2, a saltthereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, anda pharmaceutically acceptable carrier.
 11. The pharmaceuticalcomposition according to claim 10, which is a CRF antagonist.
 12. Thepharmaceutical composition according to claim 10, which is an agent forpreventing and/or treating CRF mediated diseases.
 13. The pharmaceuticalcomposition according to claim 12, wherein the CRF mediated diseases arepsychiatric and neurologic disorders or digestive diseases.
 14. Thepharmaceutical composition according to claim 13, wherein thepsychiatric and neurologic disorders or the digestive diseases are mooddisorders, anxiety disorders, stress-related disorders, eatingdisorders, symptom caused by psychotropic substance or dependencythereon, organic mental disorder, schizophrenic disorder,attention-deficit hyperactivity disorder or irritable bowel syndrome.15. The pharmaceutical composition according to claim 14, wherein thepsychiatric and neurologic disorders or the digestive diseases aredepression, mood disorders, eating disorders, drug addiction, drugdependency or irritable bowel syndrome.
 16. A medicament comprising acombination of the compound represented by formula (I-A) according toclaim 2, a salt thereof, an N-oxide thereof, a solvate thereof or aprodrug thereof with at least one selected from a tricyclicantidepressant, a tetracyclic antidepressant, a monoamine oxidaseinhibitor, a serotonin and noradrenaline reuptake inhibitor, a selectiveserotonin reuptake inhibitor, a serotonin reuptake inhibitor, apsychoanaleptic, an antianxiety agent, an antipsychotic agent, amitochondrial benzodiazepine receptor ligand, an NK1 antagonist, agastrointestinal promotility agent, a 5-HT₃ antagonist, a 5-HT₄ agonist,an anticholinergic agent, an antidiarrheal drug, a lapactic and anautonomic modulating agent.
 17. A method for antagonizing CRF, whichcomprises administering to a mammal an effective amount of the compoundrepresented by formula (I), a salt thereof, an N-oxide thereof, asolvate thereof or a prodrug thereof:

wherein all symbols have the same meanings as described in claim
 1. 18.A method for preventing and/or treating a CRF mediated disease, whichcomprises administering to a mammal an effective amount of the compoundrepresented by formula (I-A), a salt thereof, an N-oxide thereof, asolvate thereof or a prodrug thereof:

wherein all symbols have the same meanings as described in claim 2.19-20. (canceled)